1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins

ABSTRACT

The present invention relates to substituted pyrrolopyridinones and substituted pyrazolopyridinones which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

PRIORITY CLAIM

This application is a continuation of U.S. patent application Ser. No.16/994,172, filed on Aug. 14, 2020, which is a continuation of U.S.patent application Ser. No. 16/658,445, filed on Oct. 21, 2019, now U.S.Pat. No. 10,781,209, which is a continuation of U.S. patent applicationSer. No. 15/927,170, filed on Mar. 21, 2018, now U.S. Pat. No.10,472,358, which is a continuation of U.S. patent application Ser. No.15/354,223, filed on Nov. 17, 2016, now U.S. Pat. No. 9,957,268, whichis a continuation of U.S. patent application Ser. No. 14/693,424, filedon Apr. 22, 2015, now U.S. Pat. No. 9,540,368, which claims priority toU.S. Provisional Patent Application No. 61/983,289, filed on Apr. 23,2014, all of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to substituted pyrrolopyridinones andsubstituted pyrazolopyridinones which are inhibitors of BET proteinssuch as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment ofdiseases such as cancer.

BACKGROUND OF THE INVENTION

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. DNA is packaged into chromatin by wrapping around acore of histone proteins to form a nucleosome. These nucleosomes arefurther compacted by aggregation and folding to form a highly condensedchromatin structure. A range of different states of condensation arepossible, and the tightness of this structure varies during the cellcycle, being most compact during the process of cell division. Chromatinstructure plays a critical role in regulating gene transcription byregulating protein access to the DNA. The chromatin structure iscontrolled by a series of post translational modifications to histoneproteins, mainly within the tails of histones H3 and H4 that extendbeyond the core nucleosome structure. These reversible modificationsinclude acetylation, methylation, phosphorylation, ubiquitination andSUMOylation. These epigenetic marks are written and erased by specificenzymes that modify specific residues within the histone tail, therebyforming an epigenetic code. Other nuclear proteins bind to these marksand effect outputs specified by this information through the regulationof chromatin structure and gene transcription. Increasing evidence linksgenetic changes to genes encoding epigenetic modifiers and regulatorsleading to aberrant histone marks in diseases such as neurodegenerativedisorders, metabolic diseases, inflammation and cancer.

Histone acetylation is typically associated with the activation of genetranscription, as the modification weakens the interaction between theDNA and the histone proteins, permitting greater access to DNA by thetranscriptional machinery. Specific proteins bind to acetylated lysineresidues within histones to “read” the epigenetic code. A highlyconserved protein module called the bromodomain binds to acetylatedlysine residues on histone and other proteins. There are more than 60bromodomain-containing proteins in the human genome.

The BET (Bromodomain and Extra-Terminal) family of bromodomaincontaining proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t)that share a conserved structural organization containing tandemN-terminal bromodomains capable of binding to acetylated lysine residuesof histones and other proteins. BRD2, BRD3 and BRD4 are ubiquitiouslyexpressed while BRDt is restricted to germ cells. BRD proteins playessential, but non-overlapping roles in regulating gene transcriptionand controlling cell growth. BET proteins are associated with largeprotein complexes including Mediator, PAFc and super elongation complexthat regulate many aspects of gene transcription. BRD2 and BRD4 proteinshave been shown to remain in complex with chromosomes during mitosis andare required to promote transcription of critical genes including cyclinD and c-Myc that initiate the cell cycle (Mochizuki J Biol. Chem. 2008283:9040-9048). BRD4 is essential for recruiting the proteintranslational elongation factor B complex to the promoters of induciblegenes resulting in the phosphorylation of RNA polymerase II andstimulating productive gene transcription and elongation (Jang et al.Mol. Cell 2005 19:523-534). In some instances, a kinase activity of BRD4may directly phosphorylate and activate RNA polymerase II (Devaiah etal. PNAS 2012 109:6927-6932). Cells lacking BRD4 show impairedprogression through cell cycle. BRD2 and BRD3 are reported to associatewith histones along actively transcribed genes and may be involved infacilitating transcriptional elongation (Leroy et al, Mol. Cell. 200830:51-60). In addition to acetylated histones, BET proteins have beenshown to bind selectively to acetylated transcription factors includingthe RelA subunit of NF-kB and GATA1 thereby directly regulating thetranscriptional activity of these proteins to control expression ofgenes involved in inflammation and hematopoietic differentiation (Huanget al, Mol. Cell. Biol. 2009 29:1375-1387; Lamonica Proc. Nat. Acad.Sci. 2011 108:E159-168).

A recurrent translocation involving NUT (nuclear protein in testes) withBRD3 or BRD4 to form a novel fusion oncogene, BRD-NUT, is found in ahighly malignant form of epithelial neoplasia (French et al, CancerResearch 2003 63:304-307; French et al, Journal of Clinical Oncology2004 22:4135-4139). Selective ablation of this oncogene restores normalcellular differentiation and reverses the tumorigenic phenotype(Filippakopoulos et al, Nature 2010 468:1068-1073). Genetic knockdown ofBRD2, BRD3 and BRD4 has been shown to impair the growth and viability ofa wide range of hematological and solid tumor cells (Zuber et al, Nature2011 478:524-528; Delmore et al, Cell 2011 146:904-917). Aside from arole in cancer, BET proteins regulate inflammatory responses tobacterial challenge, and a BRD2 hypomorph mouse model showeddramatically lower levels of inflammatory cytokines and protection fromobesity induced diabetes (Wang et al Biochem J. 2009 425:71-83; Belkinaet al. J. Immunol 2013). In addition, some viruses make use of these BETproteins to tether their genomes to the host cell chromatin, as part ofthe process of viral replication or use BET proteins to facilitate viralgene transcription and repression (You et al, Cell 2004 117:349-60; Zhuet al, Cell Reports 2012 2:807-816).

Accordingly, there is a need for compounds that modulate the activity ofthe BET family of proteins, including BRD2, BRD3, and BRD4, that can beused to treat BET protein-associated diseases such as cancer. Thecompounds of the invention help meet this need.

SUMMARY OF THE INVENTION

The present invention relates to, inter alfa, an inhibitor of a BETprotein, wherein the inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables aredefined herein.

The present invention further relates to a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable carrier.

The present invention further relates to a method of treating a diseaseor condition that is associated with a BET protein, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION

The present invention relates to, inter alfa, an inhibitor of a BETprotein, wherein the inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is C═O or CR⁸R⁹;

Y is O, S, or NR¹⁰;

Z is CH or N;

R¹ and R² are each independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy¹, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom R^(A);

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₁₀ cycloalkyl group or a 4-10 membered heterocycloalkyl group,each optionally substituted with 1, 2, or 3 substituents independentlyselected from R^(A);

R³ is H or C₁₋₆ alkyl optionally substituted with 1, 2, or 3substituents independently selected from halo, Cy, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R⁴ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), or S(O)₂NR^(c3)R^(d3);

R⁵ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,Cy², CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),or S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(B);

R⁶ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CN, or OH;

R⁷ is H or C₁₋₄ alkyl;

R⁸ and R⁹ are each independently selected from H, halo, C₁₋₄ alkyl, andC₁₋₄ haloalkyl;

R¹⁰ is H or C₁₋₄ alkyl;

each R^(A) is independently selected from Cy¹, halo, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

each R^(B) is independently selected from Cy², halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each Cy is independently selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each ofwhich is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from R^(C);

each R^(C) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), S(O)NR^(c2)R^(d2), and S(O)₂NR^(c2)R^(d2);

each Cy¹ is independently selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each ofwhich is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from R^(D);

each R^(D) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

each Cy² is independently selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each ofwhich is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from R^(E);

each R^(E) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), (═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein in said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

each R^(a3), R^(b3), R^(c3), and R^(d3) is independently selected from Hand C₁₋₄ alkyl;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)C(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; and

each R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is independentlyselected from H, C₁₋₄ alkyl, and CN.

In some embodiments, X is C═O

In some embodiments, X is CR⁸R⁹.

In some embodiments, Y is O.

In some embodiments, Y is NR¹⁰.

In some embodiments, Z is CH.

In some embodiments, Z is N.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₆ alkyl, and Cy¹, wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from R^(A);

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₁₀ cycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from R^(A).

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₃ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl, wherein said C₆₋₁₀ aryl is optionallysubstituted with 1 or 2 halo, and wherein said C₁₋₃ alkyl is optionallysubstituted by OH;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆ cycloalkyl group.

In some embodiments, R¹ and R² are each independently selected from H,methyl, ethyl, propyl, cyclopropyl, cyclopentyl, pyran-4-yl, phenyl,pyridin-2-yl, 2-chloro-4-phenyl, and 2-hydroxyethyl.

In some embodiments, R¹ and R² together with the carbon atom to whichthey are attached form cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

In some embodiments, one of R¹ and R² is H and the other is not H.

In some embodiments, R¹ and R² are each C₁₋₆ alkyl.

In some embodiments, R¹ and R² are each methyl.

In some embodiments, R³ is H or C₁₋₆ alkyl optionally substituted with1, 2, or 3 substituents independently selected from Cy,C(═O)NR^(c2)R^(d2), and C(═O)OR^(a2).

In some embodiments, R³ is H, methyl, ethyl, or propyl, wherein saidmethyl is optionally substituted with cyclopropyl, pyridinyl,—C(═O)NHCH₃, —C(═O)NH(4-methylpiperazin-1-yl), or ═C(═O)OH.

In some embodiments, R³ is methyl.

In some embodiments, R⁴ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, CN, or OH.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H, C₁₋₆ alkyl, Cy², CN, NO₂, OR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), S(O)₂R^(b4), or S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(B).

In some embodiments, R⁵ is H, 1-methyl-1H-pyrazol-4-yl, 2-furyl, CN,NO₂, methoxy, —C(═O)NH₂, —C(═O)NH(CH₃), —C(═O)N(CH₃)₂,—C(═O)-(morpholin-4-yl), —C(═O)CH₃, —CH₂OH, —CH₂OCH₃, —CH₂NH₂,—CH₂NHSO₂(CH₂CH₃), —CH₂NHC(═O)CH₃, —CH(OH)CH₃, —SO₂CH₃, —SO₂CH₂CH₃,—SO₂-(isopropyl), —SO₂N(CH₃)₂, —SO₂NH(CH₃), —SO₂—NH(isopropyl), or—SO₂-(piperidin-1-yl).

In some embodiments, R⁵ is S(O)₂R^(b4).

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is C₁₋₄ alkyl.

In some embodiments, R⁷ is methyl.

In some embodiments, R⁸ and R⁹ are each H.

In some embodiments, R¹⁰ is H.

In some embodiments, the compound of the invention has Formula IIa:

In some embodiments, where the compound of the invention has FormulaIIa, Z is CH.

In some embodiments, where the compound of the invention has FormulaIIa, Z is N.

In some embodiments, where the compound of the invention has FormulaIIa, R¹ and R² are each independently selected from H, C₁₋₆ alkyl, andCy¹, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from R^(A);

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆ cycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from R^(A)

In some embodiments, where the compound of the invention has FormulaIIa, R¹ and R² are each independently selected from H, C₁₋₃ alkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, wherein said C₆₋₁₀ aryl is optionally substituted with1 or 2 halo, and wherein said C₁₋₃ alkyl is optionally substituted byOH;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆ cycloalkyl group.

In some embodiments, where the compound of the invention has FormulaIIa, and R² are each independently selected from H, methyl, ethyl,propyl, cyclopropyl, cyclopentyl, pyran-4-yl, phenyl, pyridin-2-yl,2-chloro-4-phenyl, and 2-hydroxyethyl.

In some embodiments, where the compound of the invention has FormulaIIa, R¹ and R² together with the carbon atom to which they are attachedform cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, where the compound of the invention has FormulaIIa, R¹ and R² together with the carbon atom to which they are attachedform cyclopropyl.

In some embodiments, where the compound of the invention has FormulaIIa, one of R¹ and R² is H and the other is not H.

In some embodiments, where the compound of the invention has FormulaIIa, R¹ and R² are each C₁₋₆ alkyl.

In some embodiments, where the compound of the invention has FormulaIIa, R¹ and R² are each methyl.

In some embodiments, where the compound of the invention has FormulaIIa, R³ is H or C₁₋₆ alkyl optionally substituted with 1, 2, or 3substituents independently selected from Cy, C(═O)NR^(c2)R^(d2), andC(═O)OR^(a2).

In some embodiments, where the compound of the invention has FormulaIIa, R³ is H, methyl, ethyl, or propyl, wherein said methyl isoptionally substituted with cyclopropyl, pyridinyl, —C(═O)NHCH₃,—C(═O)NH(4-methylpiperazin-1-yl), or —C(═O)OH.

In some embodiments, where the compound of the invention has FormulaIIa, R³ is methyl.

In some embodiments, where the compound of the invention has FormulaIIa, R³ is ethyl.

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is H, C₁₋₆ alkyl, Cy¹, CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), S(O)₂R^(b4), or S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(B).

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is H, 1-methyl-1H-pyrazol-4-yl, 2-furyl, CN, NO₂, methoxy,—C(═O)NH₂, —C(═O)NH(CH₃), —C(═O)N(CH₃)₂, —C(═O)-(morpholin-4-yl),—C(═O)CH₃, —CH₂OH, —CH₂OCH₃, —CH₂NH₂, —CH₂NHSO₂(CH₂CH₃), —CH₂NHC(═O)CH₃,—CH(OH)CH₃, —SO₂CH₃, —SO₂CH₂CH₃, —SO₂-(isopropyl), —SO₂N(CH₃)₂,—SO₂NH(CH₃), —SO₂—NH(isopropyl), or —SO₂-(piperidin-1-yl).

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is S(O)₂R^(b4).

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is S(O)₂CH₃.

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is S(O)₂CH₂CH₃.

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is —C(═O)NH₂.

In some embodiments, where the compound of the invention has FormulaIIa, R⁵ is —CH₂OCH₃.

In some embodiments, where the compound of the invention has FormulaIIa, R⁷ is methyl.

In some embodiments, the compound of the invention has Formula IIb:

In some embodiments, where the compound of the invention has FormulaIIb, Z is CH.

In some embodiments, where the compound of the invention has FormulaIIb, Z is N.

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² are each independently selected from H, C₁₋₆ alkyl, andCy¹, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from R^(A);

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₁₀ cycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from R^(A).

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² are each independently selected from H, C₁₋₃ alkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, wherein said C₆₋₁₀ aryl is optionally substituted with1 or 2 halo, and wherein said C₁₋₃ alkyl is optionally substituted byOH;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆ cycloalkyl group.

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² are each independently selected from H, methyl, ethyl,propyl, cyclopropyl, cyclopentyl, pyran-4-yl, phenyl, pyridin-2-yl,2-chloro-4-phenyl, and 2-hydroxyethyl.

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² together with the carbon atom to which they are attachedform cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² together with the carbon atom to which they are attachedform cyclopropyl.

In some embodiments, where the compound of the invention has FormulaIIb, one of R¹ and R² is H and the other is not H.

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² are each C₁₋₆ alkyl.

In some embodiments, where the compound of the invention has FormulaIIb, R¹ and R² are each methyl.

In some embodiments, where the compound of the invention has FormulaIIb, R³ is H or C₁₋₆ alkyl.

In some embodiments, where the compound of the invention has FormulaIIb, R³ is H or methyl.

In some embodiments, where the compound of the invention has FormulaIIb, R⁵ is H or S(O)₂R^(b4).

In some embodiments, where the compound of the invention has FormulaIIb, R⁵ is H or —SO₂CH₃.

In some embodiments, where the compound of the invention has FormulaIIb, R⁵ is H or —SO₂CH₂CH₃.

In some embodiments, where the compound of the invention has FormulaIIb, R⁷ is methyl.

In some embodiments, where the compound of the invention has FormulaIIb, R¹⁰ is H.

In some embodiments, the compound of the invention has Formula IIIa orIIIb:

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² are each independently selected from H, C₁₋₆alkyl, and Cy¹, wherein said C₁₋₆ alkyl is optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from R^(A);

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₁₀ cycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from R^(A).

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² are each independently selected from H, C₁₋₃alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl, wherein said C₆₋₁₀ aryl is optionallysubstituted with 1 or 2 halo, and wherein said C₁₋₃ alkyl is optionallysubstituted by OH;

or R¹ and R² together with the carbon atom to which they are attachedform a C₃₋₆ cycloalkyl group.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² are each independently selected from H, methyl,ethyl, propyl, cyclopropyl, cyclopentyl, pyran-4-yl, phenyl,pyridin-2-yl, 2-chloro-4-phenyl, and 2-hydroxyethyl.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² together with the carbon atom to which they areattached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² together with the carbon atom to which they areattached form cyclopropyl.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, one of R¹ and R² is H and the other is not H.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² are each C₁₋₆ alkyl.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R¹ and R² are each methyl.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R³ is H or C₁₋₆ alkyl optionally substituted with 1, 2, or3 substituents independently selected from Cy, C(═O)NR^(c2)R^(d2), andC(═O)OR^(a2).

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R³ is H, methyl, ethyl, or propyl, wherein said methyl isoptionally substituted with cyclopropyl, pyridinyl, —C(═O)NHCH₃,—C(═O)NH(4-methylpiperazin-1-yl), or —C(═O)OH.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R³ is methyl.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R⁵ is H, C₁₋₆ alkyl, Cy², CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), S(O)₂R^(b4), or S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(B).

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R⁵ is H, 1-methyl-1H-pyrazol-4-yl, 2-furyl, CN, NO₂,methoxy, —C(═O)NH₂, —C(═O)NH(CH₃), —C(═O)N(CH₃)₂,—C(═O)-(morpholin-4-yl), —C(═O)CH₃, —CH₂OH, —CH₂OCH₃, —CH₂NH₂,—CH₂NHSO₂(CH₂CH₃), —CH₂NHC(═O)CH₃, —CH(OH)CH₃, —SO₂CH₃, —SO₂CH₂CH₃,—SO₂-(isopropyl), —SO₂N(CH₃)₂, —SO₂NH(CH₃), —SO₂—NH(isopropyl), or—SO₂-(piperidin-1-yl).

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R⁵ is S(O)₂R^(b4).

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R⁵ is S(O)₂CH₃.

In some embodiments, where the compound of the invention has FormulaIIIa or IIIb, R⁵ is S(O)₂CH₂CH₃.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(i-j)” indicates a range whichincludes the endpoints, wherein i and j are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “z-membered” (where z is an integer) typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

The term “carbon” refers to one or more carbon atoms.

As used herein, the term “C_(i-j) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbons. In some embodiments, thealkyl group of the alkoxy group has 1 to 3 carbon atoms. Example alkoxygroups include methoxy, ethoxy, and propoxy (e.g., n-propoxy andisopropoxy).

As used herein, “C_(i-j) alkenyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore double carbon-carbon bonds and having i to j carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(i-j) alkynyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore triple carbon-carbon bonds and having i to j carbons. In someembodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkynyl groups include, but are not limited to, ethynyl,propyn-1-yl, propyn-2-yl, and the like.

As used herein, the term “C_(i-j) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkylamino groups include, but are not limited to, methylamino,ethylamino, and propylamino.

As used herein, the term “di-C_(i-j)alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each of the two alkyl groups has, independently, i to j carbonatoms. In some embodiments, each alkyl group independently has 1 to 6, 1to 4, or 1 to 3 carbon atoms. In some embodiments, the dialkylaminogroup is —N(C₁₋₄ alkyl)₂ such as, for example, dimethylamino,diethylamino, N-methyl-N-ethylamino, or N-methyl-N-propylamino.

As used herein, the term “C_(i-j) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylthio group is C₁₋₄ alkylthio such as, for example, methylthioor ethylthio.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 ormore fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, arylis C₆₋₁₀ aryl. In some embodiments, the aryl group is a naphthalene ringor phenyl ring. In some embodiments, the aryl group is phenyl.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups (—C═C—) as part of thering structure. Cycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e.,, having a bond in common with) to the cycloalkylring, for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. One or more ring- forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl, C₃₋₆cycloalkyl, or C₅₋₆ cycloalkyl. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and thelike. Further exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Further exemplary cycloalkylgroups include cyclopropyl.

As used herein, “C_(i-j) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having i toj carbon atoms. In some embodiments, the haloalkoxy group is fluorinatedonly. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms. In some embodiments, the haloalkoxy group is C₁₋₄haloalkoxy. An example haloalkoxy group is OCF₃. An additional examplehaloalkoxy group is OCHF₂.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2or more fused rings) aromatic heterocylic moiety, comprising carbonatoms and one or more heteroatom ring members selected from nitrogen,sulfur and oxygen. In some embodiments, the heteroaryl group has 1, 2,3, or 4 heteroatom ring members. In some embodiments, the heteroarylgroup has 1, 2, or 3 heteroatom ring members. In some embodiments, theheteroaryl group has 1 or 2 heteroatom ring members. In someembodiments, the heteroaryl group has 1 heteroatom ring member. In someembodiments, the heteroaryl group is 5- to 10-membered or 5- to6-membered. In some embodiments, the heteroaryl group is 5-membered. Insome embodiments, the heteroaryl group is 6-membered.

When the heteroaryl group contains more than one heteroatom ring member,the heteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.Example heteroaryl groups include, but are not limited to, pyridine,pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole,isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole,tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene,benzofuran, benzisoxazole, imidazo[1,2-b]thiazole, purine, triazine, andthe like.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms comprising wherein one or more of the ring-forming atoms areindependently selected from N, O, and S. In some embodiments, the5-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. Insome embodiments, the 5-membered heteroaryl group has 1 or 2 heteroatomring members. In some embodiments, the 5-membered heteroaryl group has 1heteroatom ring member. Example ring-forming members include CH, N, NH,O, and S. Example five-membered ring heteroaryls are thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and1,3,4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more of the ring-forming atoms is N. In someembodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatomring members. In some embodiments, the 6-membered heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the 6-memberedheteroaryl group has 1 heteroatom ring member. Example ring-formingmembers include CH and N. Example six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic heterocyclic ringsystem, which may optionally contain one or more unsaturations as partof the ring structure, and which comprises carbon atoms and at least oneheteroatom ring member independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heterocycloalkyl group has 1, 2, 3, or4 heteroatom ring members. In some embodiments, the heterocycloalkylgroup has 1, 2, or 3 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1 or 2 heteroatom ring members. In someembodiments, the heterocycloalkyl group has 1 heteroatom ring member.When the heterocycloalkyl group contains more than one heteroatom in thering, the heteroatoms may be the same or different. Example ring-formingmembers include CH, CH₂, C(O), N, NH, O, S, S(O), and S(O)₂.Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2,3 or 4 fused rings) ring systems, including spiro systems. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenon-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline,dihydrobenzofuran and the like. The carbon atoms or heteroatoms in thering(s) of the heterocycloalkyl group can be oxidized to form acarbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized. In some embodiments, heterocycloalkylis 5- to 10-membered, 4- to 10-membered, 4- to 7-membered, 4-membered,5-membered, 6-membered, or 7-membered. Examples of heterocycloalkylgroups include 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran,azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, and pyran.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofa-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminium hydride);DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC(flash column chromatography); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography—mass spectrometry); LDA (lithium diisopropylamide); m(multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone);NMR (nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); s (singlet); t(triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary);tt (triplet of triplets); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety.

Compounds of the invention can be prepared as shown in Scheme I. Theintermediate (i), where X¹ is halo, can be coupled with (ii), where M isa boronic acid, boronic ester, or an appropriately substituted metalsuch as Sn(Bu)₄ or Zn, under standard Suzuki conditions or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., abicarbonate or carbonate base) or standard Negishi conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a protected derivative(iii). The protecting group (e.g., P is tosyl or SEM) can be removedunder standard conditions (e.g., NaOH for tosyl deprotection and TFA forSEM deprotection) to give compounds of the invention.

Alternatively, the X¹ halo group of (i) can be converted to anappropriate substituted metal (iv) (e.g., M is B(OH)₂, Sn(Bu)₄, or Zn)and then coupled to a heterocyclic halide (v) (X¹ is halo) understandard Suzuki conditions or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give protected derivative(iii) which can be deprotected to yield compounds of the invention.

Compounds of the invention can be prepared as shown in Scheme II. Thenitro-phenol (i) can be halogenated with suitable reagents, such asN-chlorosuccinimide, N-bromosuccinimide, Br₂ or N-iodosuccinimide togive a halide where X¹=Cl, Br or I, and subsequent reduction of thenitro group under standard conditions (e.g., Fe or Zn) can give theamino intermediate (ii). Alkylation of (ii) with X²C(═O)C(R¹R²)-Br(iii), where X² is C₁₋₄ alkoxy such as ethoxy, using standard alkylatingconditions can give an ether which can cyclize in situ or upon heatingto afford the bicyclic derivative (iv). Alternatively, acylation of theamine of (ii) with BrC═OCR¹R²-Br (iii) under standard acylatingconditions can give an amide which can cyclize in situ or upon heatingto afford the bicyclic derivative (iv). After an optional N-akylationstep to introduce R³, the compounds (iv) can be coupled withintermediates (v), where M is a boronic acid, boronic ester, or anappropriately substituted metal such as Sn(Bu)₄ or Zn, under standardSuzuki conditions or standard Stille conditions as mentioned above togive a protected derivative (vi). Alternatively, introduction of R³ viaalkylation can be carried out after the formation of derivative (vi).For example, pyridone (vi) can be alkylated by reacting with R³-X¹,where X¹=halo (Br, Cl, or I), and a base, such as triethylamine, NaH orNa₂CO₃, and subsequently deprotecting under standard conditions (e.g.,NaOH for tosyl deprotection and TFA for SEM deprotection) to affordcompounds of the invention (vii).

Optionally, reduction of the carbonyl of (iv) with a reducing agent,such as borane, followed by alkylation with R³-X¹ and a base can givecompounds of the invention (ix). These compounds can be coupled with (v)under standard Suzuki conditions or standard Stille conditions to give aprotected derivative which can be subsequently deprotected understandard conditions to afford compounds of the invention (viii).

Compounds of the invention can be formed as shown in Scheme III. Thenitro compound (i) can be halogenated with suitable reagents, such asN-chlorosuccinimide, N-bromosuccinimide or Br₂ or N-iodosuccinimide togive a halide where X¹=Cl, Br or I. Reaction of the nitro-halide (ii)with an ester (iii), such as RO₂CCR¹R²-Y¹ (where R is C₁₋₄ alkyl and Y¹is OH or NR¹⁰), can give a nitro-intermediate derivative which uponreduction of the nitro group under standard conditions (e.g., Fe or Zn)can give the corresponding amine which can then cyclize in situ or uponheating to afford bicyclic derivative (iv). The intermediate (iv) can becoupled to (v), where M is a boronic acid, boronic ester or anappropriately substituted metal such as Sn(Bu)₄ or Zn, under standardSuzuki conditions or standard Stille conditions to give protectedderivative (vi). Pyridone (vi) can be alkylated by reacting with R³-X¹where X¹=Br, Cl, or I and a base, such as triethylamine, NaH or Na₂CO₃.Then deprotection can be carried out under standard conditions to affordcompounds of the invention (vii).

Optionally, compound (iv) can be first alkylated with R³-X¹, thencoupled to (v), under standard Suzuki conditions or standard Stilleconditions to give a protected derivative (vi). Then deprotection can becarried out under standard conditions to afford compounds of theinvention (vii). Reduction of the carbonyl of (vii) with a reducingagent, such as borane, can give compounds of the invention (viii).

Intermediates for making compounds of the invention can be prepared asshown in Scheme IV. A thiophenol (i) can be alkylated with R^(b4)X¹(where X¹=Br, Cl, or I) and a base, such as triethylamine, NaH orNa₂CO₃) to afford a thioether which can be oxidized with a suitablereagent, such as mCPBA or H₂O₂ or dioxirane, to give the sulfoxide whichcan be further oxidized with an oxidant, such as mCPBA or H₂O₂ ordioxirane, to give a sulfone (ii). The sulfone (ii) can be nitratedunder standard conditions (e.g., HNO₃ with or without Fe or H₂SO₄catalyst) to give a nitro-phenol (iii). Compounds of the invention canbe synthesized from intermediates (iii) using the methods described inScheme II.

Compounds of the invention can be prepared as shown in Scheme V. Acyanophenol (i) can be reduced with suitable reagents (e.g., LiBH₄ orborane) to give amines (ii) which can be acylated, arylated or alkylatedunder standard conditions. Alternatively, cyanophenol (i) can be reducedto an aldehyde (v) with a reducing agent, such as DIBAL, and thenreductively aminated under standard conditions (e.g., NaCNBH₄, HNRRwhere each R is independently, e.g., C₁₋₆ alkyl, —C(═O)(C₁₋₆ alkyl),cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or substitutedderivatives thereof and the like) to give an amino derivative (iii). Thealdehyde (v) can also be alkylated under standard conditions (e.g.,Grignard reagent of formula R-MgX¹ (X¹=halo)) to give an alcohol (vi)which can be converted to a leaving group, such as a mesylate, anddisplaced with an amine, HNRR, to give a derivative (iii). In addition,cyanophenol (i) can be hydrolyzed to its carboxylic acid (iv) and thencoupled to an amine, HNRR, using standard amide coupling agents (e.g.,HBTU, HATU or EDC) to give an amide (vii). Compounds of the inventioncan be synthesized from these nitrophenol derivatives (i-vii) using themethods described in Scheme II.

Compounds of the invention can be prepared as shown in Scheme VI. Thehalide derivative (i) can be coupled to M-R⁵, where M is a boronic acid,boronic ester or an appropriately substituted metal Sn(Bu)₄ or Zn—R⁵under standard Suzuki conditions or standard Stille conditions to give aderivative (ii). M-R⁵ can also be an amine containing heterocycle (whereM is H and is attached to the amine nitrogen of heterocycle R⁵) withcoupling to the halide of (i) being performed by heating with a base orunder Buchwald/Hartwig conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to give derivative (ii). Compoundsof the invention can be synthesized from (ii) using the methodsdescribed in Scheme II.

Intermediates for preparing compounds of the invention can be made asshown in Scheme VII. Pyridyl derivative (i) can be reacted with1,1-dimethoxy-N,N-dimethylmethanamine to give olefin (ii). Reduction ofthe nitro group under standard conditions (e.g., Fe or Zn) gives anamino compound which may cyclize in situ or upon heating to afford abicyclic derivative (iii). The amino group of (iii) can be protectedwith a suitable protecting group P, where for example P is tosyl or SEM,under standard conditions (e.g., tosyl-Cl or SEM-Cl) to give theprotected heterocycle (iv). Acid hydrolysis of the ether and alkylationof the amide with R⁷—X¹ under standard conditions (where X¹=halo) and abase, such as triethylamine, NaH or Na₂CO₃) can afford pyridone (v).Conversion of the bromide of (v) to a metal (e.g., M is B(OR)₂, SnR₃,Zn) under standard conditions can give intermediates (vi). Compounds ofthe invention can be synthesized from (vi) using methods described inScheme I-III (See also, WO 2013/097601, p. 92),

Intermediates for the preparation of compounds of the invention can bemade as shown in Scheme VIII. Pyridyl derivative (i) can be alkylatedwith R⁷—X¹ under standard conditions (where X¹=Br, Cl, or I) and a base,such as triethylamine, NaH or Na₂CO₃) to give a pyridone (ii). Reductionof the nitro of (ii) under standard conditions (e.g., Fe or Zn) can givean amino compound which upon reaction with amyl nitrite can cyclize insitu or upon heating to afford a bicyclic derivative (iv). Theheterocyclic amine (iv) can be protected with a suitable protectinggroup under standard conditions (e.g., tosyl-Cl or SEM-Cl) to give theprotected heterocycle (v). Conversion of the bromide (v) to a metal M(e.g., M is B(OR)₂, SnR₃, Zn) under standard conditions can giveintermediates (vi). Compounds of the invention can be synthesized fromintermediate (vi) using methods described in Scheme I-III (See also, WO2013/097601, p. 92).

For the synthesis of particular compounds, the general schemes describedabove can be modified. For example, the products or intermediates can bemodified to introduce particular functional groups. Alternatively, thesubstituents can be modified at any step of the overall synthesis bymethods know to one skilled in the art, e.g., as described by Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPreparations (Wiley, 1999); and Katritzky et al. (Ed.), ComprehensiveOrganic Functional Group Transformations (Pergamon Press 1996).

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

Methods of Use

Compounds of the invention are BET protein inhibitors and, thus, areuseful in treating diseases and disorders associated with activity ofBET proteins. For the uses described herein, any of the compounds of theinvention, including any of the embodiments thereof, may be used.

The compounds of the invention can inhibit one or more of BET proteinsBRD2, BRD3, BRD4, and BRD-t. In some embodiments, the compounds of theinvention selectively inhibit one or more BET proteins over another.“Selective” means that the compound binds to or inhibits a BET proteinwith greater affinity or potency, respectively, compared to a reference,such as another BET protein. For example, the compounds can be selectivefor BRD2 over BRD3, BRD4 and BRD-t, selective for BRD3 over BRD2, BRD4and BRD-t, selective for BRD4 over BRD2, BRD3 and BRD-t, or selectivefor BRD-t over BRD2, BRD3 and BRD4. In some embodiments, the compoundsinhibit two or more of the BET proteins, or all of the BET proteins. Ingeneral, selectivity can be at least about 5-fold, at least about10-fold, at least about 20-fold, at least about 50-fold, at least about100-fold, at least about 200-fold, at least about 500- fold or at leastabout 1000-fold.

The compounds of the invention are therefore useful for treating BETprotein mediated disorders. The term “BET-mediated” refers to anydisease or condition in which one or more of the BET proteins, such asBRD2, BRD3, BRD4 and/or BRD-t, or a mutant thereof, plays a role, orwhere the disease or condition is associated with expression or activityof one or more of the BET proteins. The compounds of the invention cantherefore be used to treat or lessen the severity of diseases andconditions where BET proteins, such as BRD2, BRD3, BRD4, and/or BRD-t,or a mutant thereof, are known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude, but are not limited to, cancer and other proliferativedisorders, autoimmune disease, chronic inflammatory diseases, acuteinflammatory diseases, sepsis, and viral infection. The diseases can betreated by administering to an individual (e.g., a patient) in need ofthe treatment a therapeutically effective amount or dose of a compoundof the invention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof. The present disclosure also provides a compound ofthe invention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof, for use in treating a BET-mediated disease ordisorder. Also provided is the use of a compound of the invention, orany of the embodiments thereof, or a pharmaceutical composition thereof,in the manufacture of a medicament for treating a BET-mediated diseaseor disorder.

Diseases that can be treated with the compounds of the invention includecancers. The cancers can include, but are not limited to, adrenalcancer, acinic cell carcinoma, acoustic neuroma, acral lentiginousmelanoma, acrospiroma, acute eosinophilic leukemia, acute erythroidleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia,acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma,adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor,adenosquamous carcinoma, adipose tissue neoplasm, adrenocorticalcarcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia,AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft partsarcoma, ameloblastic fibroma, anaplastic large cell lymphoma,anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocyticleukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer,bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma insitu, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, primary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma,retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation,rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor,sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer,small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,somatostatinoma, soot wart, spinal tumor, splenic marginal zonelymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease,small intestine cancer, squamous carcinoma, stomach cancer, T-celllymphoma, testicular cancer, thecoma, thyroid cancer, transitional cellcarcinoma, throat cancer, urachal cancer, urogenital cancer, urothelialcarcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visualpathway glioma, vulvar cancer, vaginal cancer, Waldenstrom'smacroglobulinemia, Warthin's tumor, and Wilms' tumor. In someembodiments, the cancer can be adenocarcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectalcancer, esophageal cancer, gastrointestinal cancer, glioblastomamultiforme, glioma, gallbladder cancer, gastric cancer, head and neckcancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer,kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, livercancer, small cell lung cancer, non-small cell lung cancer,mesothelioma, multiple myeloma, acute myeloid leukemia (AML), diffuselarge B-cell lymphoma (DLBCL), ocular cancer, optic nerve tumor, oralcancer, ovarian cancer, pituitary tumor, primary central nervous systemlymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renalcell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, smallintestine cancer, stomach cancer, T-cell lymphoma, testicular cancer,thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma,uterine cancer, vaginal cancer, or Wilms' tumor.

In some embodiments, the cancer is a hematological cancer.

In some embodiments, the cancer is multiple myeloma, acute myeloidleukemia (AML), or diffuse large B-cell lymphoma (DLBCL).

The diseases treatable using the compounds of the invention also includeMYC dependent cancers wherein the cancer is associated with at least oneof myc RNA expression or MYC protein expression. A patient can beidentified for such treatment by determining myc RNA expression or MYCprotein expression in the cancerous tissue or cells.

Diseases that can be treated with compounds of the invention alsoinclude non-cancerous proliferative disorders. Examples of proliferativedisorders that can be treated include, but are not limited to, benignsoft tissue tumors, bone tumors, brain and spinal tumors, eyelid andorbital tumors, granuloma, lipoma, meningioma, multiple endocrineneoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumorcerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cysticneoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, andcysts, Castleman disease, chronic pilonidal disease, dermatofibroma,pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.

The diseases and conditions that can be treated with the compounds ofthe invention also include chronic autoimmune and inflammatoryconditions. Examples of autoimmune and inflammatory conditions that canbe treated include acute, hyperacute or chronic rejection oftransplanted organs, acute gout, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),Addison's disease, agammaglobulinemia, allergic rhinitis, allergy,alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma,osteoarthritis, juvenile arthritis, psoriatic arthritis, rheumatoidarthriti, satopic dermatitis, autoimmune alopecia, autoimmune hemolyticand thrombocytopenic states, autoimmune hypopituitarism, autoimmunepolyglandular disease, Behcet's disease, bullous skin diseases,cholecystitis, chronic idiopathic thrombocytopenic purpura, chronicobstructive pulmonary disease (COPD), cirrhosis, degenerative jointdisease, depression, dermatitis, dermatomyositis, eczema, enteritis,encephalitis, gastritis glomerulonephritis, giant cell arteritis,Goodpasture's syndrome, Guillain-Barre syndrome, gingivitis, Graves'disease, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatorybowel disease (Crohn's disease and ulcerative colitis), inflammatorypelvic disease, irritable bowel syndrome, Kawasaki disease, LPS-inducedendotoxic shock, meningitis, multiple sclerosis, myocarditis, myastheniagravis, mycosis fungoides, myositis, nephritis, osteomyelitis,pancreatitis, Parkinson's disease, pericarditis, pernicious anemia,pneumonitis, primary biliary sclerosing cholangitis, polyarteritisnodosa, psoriasis, retinitis, scleritis, scleracierma, scleroderma,sinusitis, Sjogren's disease, sepsis, septic shock, sunburn, systemiclupus erythematosus, tissue graft rejection, thyroiditis, type Idiabetes, Takayasu's arteritis, urethritis, uveitis, vasculitis,vasculitis including giant cell arteritis, vasculitis with organinvolvement such as glomerulonephritis, vitiligo, Waldenstrommacroglobulinemia and Wegener's granulomatosis.

The diseases and conditions that can be treated with the compounds ofthe invention also include diseases and conditions which involveinflammatory responses to infections with bacteria, viruses, fungi,parasites or their toxins, such as sepsis, sepsis syndrome, septicshock, endotoxaemia, systemic inflammatory response syndrome (SIRS),multi-organ dysfunction syndrome, toxic shock syndrome, acute lunginjury, ARDS (adult respiratory distress syndrome), acute renal failure,fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes,sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis,malaria, SIRS associated with viral infections such as influenza, herpeszoster, herpes simplex and coronavirus.

Other diseases that can be treated with the compounds of the inventioninclude viral infections. Examples of viral infections that can betreated include Epstein-Barr virus, hepatitis B virus, hepatitis Cvirus, herpes virus, human immunodeficiency virus, human papillomavirus, adenovirus, poxvirus and other episome-based DNA viruses. Thecompounds can therefore be used to treat disease and conditions such asherpes simplex infections and reactivations, cold sores, herpes zosterinfections and reactivations, chickenpox, shingles, human papillomavirus, cervical neoplasia, adenovirus infections, including acuterespiratory disease, and poxvirus infections such as cowpox and smallpoxand African swine fever virus. In one particular embodiment, thecompounds of the invention are indicated for the treatment of humanpapilloma virus infections of skin or cervical epithelia.

The diseases and conditions that can be treated with the compounds ofthe invention also include conditions that are associated withischaemia-reperfusion injury. Examples of such conditions include, butare not limited to conditions such as myocardial infarction,cerebrovascular ischaemia (stroke), acute coronary syndromes, renalreperfusion injury, organ transplantation, coronary artery bypassgrafting, cardio-pulmonary bypass procedures and pulmonary, renal,hepatic, gastro-intestinal or peripheral limb embolism.

The compounds of the invention are also useful in the treatment ofdisorders of lipid metabolism via the regulation of APO-A1 such ashypercholesterolemia, atherosclerosis and Alzheimer's disease.

The compounds of the invention are also useful in the treatment offibrotic conditions such as idiopathic pulmonary fibrosis, renalfibrosis, post-operative stricture, keloid formation, scleroderma andcardiac fibrosis.

The compounds of the invention can also be used to treat ophthamologicalindications such as dry eye.

The compounds of the invention can also be used to treat heart diseasesuch as heart failure.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a BET protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a BET protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the BETprotein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinaseinhibitors for treatment of BET protein-associated diseases, disordersor conditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially. In someembodiments, the compounds of the invention can be used in combinationwith a therapeutic agent that targets an epigenetic regulator. Examplesof epigenetic regulators include the histone lysine methyltransferases,histone arginine methyl transferases, histone demethylases, histonedeacetylases, histone acetylases, and DNA methyltransferases. Histonedeacetylase inhibitors include, e.g., vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,or other anti-proliferative agents. The compounds of the invention canalso be used in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with ruxolitinib.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

In some embodiments, the compounds of the invention are administered incombination with a JAK kinase inhibitor (e.g., ruxolitinib, tofacitinib,baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, TG101348, or aJAK1-selective inhibitor), a Pim kinase inhibitor (including inhibitorsof one or more of PIM1, PIM2, and PIM3), a PI3 kinase inhibitorincluding PI3K-delta selective and broad spectrum PI3K inhibitors, anMEK inhibitor, a cyclin dependent kinase inhibitor, a b-RAF inhibitor,an mTOR inhibitor, a proteasome inhibitor (e.g., bortezomib,carfilzomib), an HDAC-inhibitor (e.g., panobinostat, vorinostat), a DNAmethyl transferase inhibitor, dexamethasone, melphalan, or animmunomodulator (e.g., lenolidomide, pomalidomide).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated.

Administration may be topical (including transdermal, epidermal,ophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal orintranasal), oral or parenteral. Parenteral administration includesintravenous, intraarterial, subcutaneous, intraperitoneal intramuscularor injection or infusion; or intracranial, e.g., intrathecal orintraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate. The liquid forms in which the compoundsand compositions of the present invention can be incorporated foradministration orally or by injection include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil, or peanut oil, as well as elixirs and similar pharmaceuticalvehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating BET proteins in tissuesamples, including human, and for identifying BET protein ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes BET protein assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro BET protein labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S willgenerally be most useful.

For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br,⁷⁶Br or ⁷⁷Br will generally be most useful.

It is to be understood that a “radio-labeled ” or “labeled compound” isa compound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a BET protein by monitoring itsconcentration variation when contacting with the BET protein, throughtracking of the labeling. For example, a test compound (labeled) can beevaluated for its ability to reduce binding of another compound which isknown to bind to a BET protein (i.e., standard compound). Accordingly,the ability of a test compound to compete with the standard compound forbinding to the BET protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled.

Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more BET proteins as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™C_(18 5 μ)m, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water andmobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes withflow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C_(18 5 μ)m, 19×100 mm column,eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in waterand mobile phase B: acetonitrile; the flow rate was 30 mL/minute, theseparating gradient was optimized for each compound using the CompoundSpecific Method Optimization protocol as described in the literature[see “Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters XBridge C_(18 5 μ)m, 19×100 mm column,eluting with mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature [See “PreparativeLCMS Purification: Improved Compound Specific Method Optimization”, K.Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Example 1.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one

Step 1. 8-bromo-2-phenyl-2H-1,4-benzoxazin-3(4H)-one

2-Amino-6-bromophenol (0.10 g, 0.53 mmol) (Frinton cat #FR-2404) andα-bromo-benzeneacetic acid methyl ester (0.084 mL, 0.53 mmol) (Aldrichcat #365270) were combined with N-methylpyrrolidinone (2.0 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.080 mL, 0.53 mmol) in a sealedtube. The mixture was heated to 140° C. in the microwave for 5 minutes.The reaction mixture was then cooled, dissolved in ethyl acetate, andwashed with 1 N HCl, brine, dried over magnesium sulfate, andconcentrated to give a dark oil. The product was purified by FCC onsilica gel eluting a hexane: ethyl acetate gradient to afford8-bromo-2-phenyl-2H-1,4-benzoxazin-3(4H)-one as a semisolid (0.1 g,60%). LCMS calculated for C₁₄H₁₁BrNO₂ (M+H)⁺: m/z=304.0, 306.0; found:303.8, 305.8.

Step 2.8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-phenyl-2H-1,4-benzoxazin-3(4H)-one

8-Bromo-2-phenyl-2H-1,4-benzoxazin-3(4H)-one (0.02 g, 0.06 mmol) wascombined with6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(0.028 g, 0.066 mmol) (WO02013097601, p. 92) in a mixture of 1,4-dioxane(1.5 mL) and potassium carbonate (0.018 g, 0.13 mmol) in water (0.50mL). The reaction was degassed with nitrogen and the catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (0.005 g, 0.006 mmol) was added. The reaction washeated in a sealed tube to 100° C. for 2 h. The mixture was cooled toroom temperature and was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over magnesium sulfate,and concentrated to afford8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-phenyl-2H-1,4-benzoxazin-3(4H)-one(0.025 g, 83%) as a dark oil. LCMS calculated for C₂₉H₂₄N₃O₅S (M+H)⁺:m/z=526.1; found: 526.1.

Step 3.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one

8-{6-Methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-phenyl-2H-1,4-benzoxazin-3(4H)-onewas dissolved in a mixture of ethanol (3.0 mL) and 1.0 M sodiumhydroxide in water (1.0 mL) and heated to 80° C. in an oil bath for 1 h.The mixture was then cooled to room temperature and acidified withtrifluoroacetic acid (TFA). The product was purified by prep HPLC on aC-18 column eluting a water:acetonitrile gradient buffered at pH 2 withTFA, to afford the title product as an off white amorphous solid (25mg). LCMS calculated for C₂₂H₁₈N₃O₃ (M+H)⁺: m/z=372.1; found: 372.1. ¹HNMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 11.03 (s, 1H), 7.28 (ddd, J=8.5,6.4, 3.9 Hz, 5H), 7.17 (t, J=2.8 Hz, 1H), 7.06 (s, 1H), 7.05-6.89 (m,3H), 6.02-5.95 (m, 1H), 5.73 (s, 1H), 3.47 (s, 3H).

Examples 2-4

The compounds of Example 2-4 and the experimental procedures used toprepare them are set out in Table 1 below.

TABLE 1

Ex. Synthetic No. Name R¹ Procedure 2 2-isopropyl-8-(6-methyl-7-oxo-6,7-i-Prop Ex. No. 1 dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one 3 2-methyl-8-(6-methyl-7-oxo-6,7- Me Ex. No.1 dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)- 2H-1,4-benzoxazin-3(4H)-one 42-ethyl-8-(6-methyl-7-oxo-6,7- Et Ex. No. 1dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)- 2H-1,4-benzoxazin-3(4H)-one

Example 5.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one2,2,2-trifluoroacetate

Step 1. Methyl bromo(pyridin-2-yl)acetate

Benzoyl peroxide (80 mg, 0.3 mmol) was added in one portion to asolution of methyl 2-pyridylacetate (500 mg, 3 mmol) (Aldrich cat#M78305) and N-bromosuccinimide (600 mg, 3 mmol) in carbon tetrachloride(5 mL). The reaction was heated to 100° C. for 1 h, cooled to roomtemperature, and filtered to remove the solids. The solvent wasevaporated to afford methyl bromo(pyridin-2-yl)acetate as dark yellowsemi-solid. LCMS calculated for C₈H₉BrNO₂ (M+H)⁺: m/z=229.9, 231.9;found=229.9, 231.8.

Step 2. 8-bromo-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one

A mixture of 2-amino-6-bromophenol (100 mg, 0.5 mmol), methylbromo(pyridin-2-yl)acetate (100 mg, 0.5 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (80 μL, 0.5 mmol) inN-methylpyrrolidinone (3 mL) was heated in microwave at 140° C. for 10min. The reaction was allowed to cool, was diluted with ethyl acetateand washed with water. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated to afford8-bromo-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one (0.15 g, 90%) as acrude product. LCMS calculated for C₁₃H₁₀BrN₂O₂ (M+H)⁺: m/z=304.9 306.9;found=305.0, 307.0.

Step 3.8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one2,2,2-trifluoroacetate

8-Bromo-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one (15 mg, 0.049 mmol)and6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(25 mg, 0.059 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL)and potassium carbonate (10 mg, 0.07 mmol) in water (0.8 mL). Thereaction was degassed with nitrogen and the catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (5 mg, 0.006 mmol) was added. The reaction washeated at 100° C. for 4 h, allowed to cool, and was partitioned betweenwater and EtOAc. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated. The product was purifiedon prep HPLC on a C-18 column eluting with a water:acetonitrile gradientbuffered at pH 2 with TFA to afford8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one2,2,2-trifluoroacetate as a white solid (0.015 g, 58%). LCMS calculatedfor C₂₈H₂₃N₄O₅S (M+H)⁺: m/z=527.1; found 527.1.

Step 4.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one2,2,2 trifluoroacetate

8-{6-Methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one2,2,2 trifluoroacetate 0.015g, 0.028 mmol) was dissolved in a mixture ofethanol (2 mL,) and 1.0 M sodium hydroxide in water (1 mL) and wasstirred at 80° C. for 2 h. The reaction mixture was purified withoutwork-up by prep HPLC on a C-18 column eluting with a water:acetonitrilegradient buffered at pH 2 with TFA to afford the title product as awhite solid (0.004 g, 30%). LCMS calculated for C₂₁H₁₇N₄O₃ (M+H)⁺:m/z=373.1; found=373.0.

Example 6.2-cyclopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. ethyl bromo(cyclopropyl)acetate

Thionyl chloride (0.46 mL, 6.3 mmol) was added dropwise to a solution ofcyclopropylacetic acid (0.5 g, 5 mmol) (Oakwood cat #003710) in1,2-dichloroethane (5.2 mL) at room temperature. The reaction was heatedto reflux for 2 h then allowed to cool to room temperature, at whichtime N-bromosuccinimide (1.12 g, 6.27 mmol) and hydrogen bromide (2 μL,0.04 mmol) (48% aqueous solution) were added successively. The resultingmixture was heated to reflux for 2 days. The reaction mixture was thencooled to room temperature, ethanol (4 mL) was added, and the reactionwas stirred at room temperature for an additional 2 h. The reactionmixture was then concentrated to afford the crude product. The crudeproduct was dissolved in carbon tetrachloride and was passed through ashort column of silica gel and concentrated to afford ethylbromo(cyclopropyl)acetate (0.70 g, 70%) as an oil.

Step 2.2-cyclopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to Example 5, but using ethylbromo(cyclopropyl)acetate, the title compound was prepared and purifiedby prep HPLC on a C-18 column eluting with a water:acetonitrile gradientbuffered at pH 2 with TFA to afford2-cyclopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-oneas a white amorphous solid (0.007 g, 40%). LCMS calculated forC₁₉H₁₈N₃O₃ (M+H)⁺: m/z=336.1; found=336.1. ¹H NMR (300 MHz, DMSO-d₆) δ11.68 (s, 1H), 10.36 (s, 1H), 6.92 (d, J=3.5 Hz, 2H), 6.66 (d, J=4.6 Hz,2H), 6.55 (q, J=4.7, 4.1 Hz, 1H), 5.83 (t, J=2.3 Hz, 1H), 3.72 (d, J=8.3Hz, 1H), 3.20 (s, 3H), 0.82 (ddt, J=13.0, 8.2, 4.3 Hz, 1H), 0.21 (t,J=9.2 Hz, 1H), 0.14-−0.05 (m, 3H).

Example 7.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. methyl tetrahydro-2H-pyran-4-ylacetate

A mixture of tetrahydro-2H-pyran-4-ylacetic acid (500 mg, 3 mmol) (CombiBlocks cat #AM-1005) and sulfuric acid (20 μL, 0.4 mmol) in methanol (10μL) was heated to reflux for 12 h. The mixture was then cooled andconcentrated to remove the methanol. The resulting residue was dissolvedin EtOAc, washed with saturated NaHCO₃, dried, and concentrated toafford methyl tetrahydro-2H-pyran-4-ylacetate (510 mg, 100%) as a crudeproduct.

Step 2. methyl bromo(tetrahydro-2H-pyran-4-yl)acetate

n-Butyllithium in hexanes 1.6 M (2 mL, 3 mmol) was added dropwise to asolution of N,N-diisopropylethylamine (0.6 mL, 3 mmol) intetrahydrofuran (5 mL) at −78° C. The reaction mixture was stirred for30 min and then added to a cold solution of methyltetrahydro-2H-pyran-4-ylacetate (500 mg, 3 mmol) in tetrahydrofuran (5mL). The mixture was stirred for 1 h, followed by addition ofchlorotrimethylsilane (0.4 mL, 3 mmol). The resulting mixture was warmedto room temperature for 1 h, cooled to −78° C., and N-bromosuccinimide(0.6 g, 3 mmol) was added. The reaction was warmed to room temperatureand stirred for an additional 2 h. The suspension was filtered through asilica gel pad, and the solids were washed with ethyl ether. The organicsolution was concentrated to give crude methylbromo(tetrahydro-2H-pyran-4-yl)acetate as an oil (0.30 g, 40%).

Step 3.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to Example 5, but using methylbromo(tetrahydro-2H-pyran-4-yl)acetate, the title compound was preparedas a white amorphous solid (0.008 g, 40%). LCMS calculated forC₂₁H₂₂N₃O₄ (M+H)⁺: m/z=380.1; found=380.2. ¹H NMR (500 MHz, DMSO-d₆) δ12.00 (s, 1H), 10.73 (s, 1H), 7.25 (d, J=3.9 Hz, 2H), 7.03-6.97 (m, 2H),6.88 (dd, J=6.6, 2.7 Hz, 1H), 6.21-6.11 (m, 1H), 4.45 (d, J=4.7 Hz, 1H),3.73 (t, J=10.8 Hz, 2H), 3.54 (s, 3H), 3.24-3.12 (m, 2H), 2.18-2.08 (m,1H), 1.46-1.26 (m, 4H).

Example 8.2-ethyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1.2-ethyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-one

2-Ethyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-one(20 mg, 0.04 mmol) of Example 4 was dissolved in N,N-dimethylformamide(1 mL), sodium hydride in mineral oil (2 mg, 0.08 mmol) was added, andthe mixture was stirred for 10 min. Methyl iodide (4 μL, 0.06 mmol) wasadded and the mixture was stirred for an additional 30 min. The reactionmixture was then partitioned between ethyl acetate and water. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, and concentrated to afford crude2-ethyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-oneas a glass (20 mg, 100%). LCMS calculated for C₂₆H₂₆N₃O₅S (M+H)⁺:m/z=492.1; found=491.9.

Step 2.2-ethyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Crude2-ethyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-one(20 mg, 0.04 mmol) was dissolved in a mixture of ethanol (2 mL) and 1.0M sodium hydroxide in water (1 mL), and the reaction mixture was heatedat 80° C. for 1 h. The reaction mixture was then purified without workupon prep LC-MS on a C-18 column eluting a water : acetonitrile gradientbuffered at pH 2 with TFA to afford2-ethyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-oneas white solid (6 mg, 40%). LCMS calculated for C₁₉H₂₀N₃O₃ (M+H)⁺:m/z=338.1; found=338.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 7.24(d, J=5.3 Hz, 2H), 7.19-7.03 (m, 3H), 6.14 (s, 1H), 4.54 (dd, J=8.0, 4.2Hz, 1H), 3.53 (s, 3H), 3.31 (s, 3H), 1.81 (dd, J=11.5, 7.2 Hz, 1H), 1.65(dt, J=14.4, 7.6 Hz, 1H), 0.76 (t, J=7.3 Hz, 3H).

Example 9.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. 8-bromo-2-isopropyl-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

2-Amino-6-bromo-4-methoxyphenol (0.1 g, 0.4 mmol) (Aldrich cat #653705)and ethyl 2-bromo-3-methylbutanoate (0.11 mL, 0.69 mmol) (Alpha cat#B22525) were combined in N-methylpyrrolidinone (1.0 mL) with1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.92 mmol) in a sealedtube. The reaction mixture was heated to 140° C. in a microwave for 15minutes. The reaction mixture was then cooled and partitioned betweenethyl acetate and 1 N HCl. The combined organic layers were washed withbrine, dried over magnesium sulfate, and concentrated to give a darkoil. The product was purified by FCC on silica gel eluting ahexane:ethyl acetate gradient to afford8-bromo-2-isopropyl-6-methoxy-2H-1,4-benzoxazin-3(4H)-one as a semisolid(0.03 g, 30%). LCMS calculated for C₁₂H₁₅BrNO₃ (M+H)⁺: m/z=300.1, 302.1;found=300.0, 302.0.

Step 2.2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-one

8-Bromo-2-isopropyl-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (0.03 g, 0.1mmol) was combined with6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(0.043 g, 0.10 mmol) in 1,4-dioxane (2.5 mL) and potassium carbonate(0.031 g, 0.22 mmol) in water (0.84 mL). The reaction was degassed withnitrogen and the catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (0.009 g, 0.01 mmol) was added. The reaction washeated in a sealed tube to 100° C. for 2 h. The mixture was then cooledto room temperature and was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over magnesium sulfate,and concentrated to afford2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-oneas a dark oil (0.03 g, 60%). LCMS calculated for C₂₇H₂₈N₃O₆S (M+H)⁺:m/z=522.1; found=522.1.

Step 3.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

2-Isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-one(0.03 g, 0.06 mol) was dissolved in a mixture of ethanol (5.1 mL) and1.0 M sodium hydroxide in water (1.7 mL) and heated to 80° C. in an oilbath for 1 h. The mixture was then cooled to room temperature andacidified with TFA. The crude product was purified by prep HPLC on aC-18 column eluting a water : acetonitrile gradient buffered at pH 2with TFA to afford the title compound as an off white amorphous solid(0.02 g, 50%). LCMS calculated for C₂₀H₂₂N₃O₄ (M+H)⁺: m/z=368.1;found=368.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 10.61 (s, 1H),7.35-7.20 (m, 2H), 6.57 (d, J=2.9 Hz, 1H), 6.45 (d, J=2.9 Hz, 1H), 6.20(d, J=2.1 Hz, 1H), 4.30 (d, J=4.3 Hz, 1H), 3.70 (s, 3H), 3.53 (s, 3H),2.28-2.09 (m, 1H), 0.80 (dd, J=11.7, 6.8 Hz, 6H).

Example 9A.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 1) Example 9B.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 2)

The enantiomers of Example 9 were separated by prep chiral columnchromatography using the following chiral separation conditions: Column:Chiralpak IA C-2 5 μm, 21, 2×250 mm; Mobile phase: 30% EtOH/Hexanes;gradient condition: isocratic at 14 mL/min; Loading: 1.0 mg in 900 μL;run time: 17 min; peak times: 11.0 and 14.4 min.

Example 9A, Peak 1 as a solid residue (11.0 min). LCMS calculated forC₂₀H₂₂N₃O₄ (M+H)⁺: m/z=368.1; found=368.1. ¹H NMR (300 MHz, DMSO-d₆) δ12.01 (s, 1H), 10.61 (s, 1H), 7.35-7.20 (m, 2H), 6.57 (d, J=2.9 Hz, 1H),6.45 (d, J=2.9 Hz, 1H), 6.20 (d, J=2.1 Hz, 1H), 4.30 (d, J=4.3 Hz, 1H),3.70 (s, 3H), 3.53 (s, 3H), 2.28-2.09 (m, 1H), 0.80 (dd, J=11.7, 6.8 Hz,6H).

Example 9B, Peak 2 as a solid residue (14.4). LCMS calculated forC₂₀H₂₂N₃O₄ (M+H)⁺: m/z=368.1; found=368.1. ¹H NMR (300 MHz, DMSO-d₆) δ12.01 (s, 1H), 10.61 (s, 1H), 7.35-7.20 (m, 2H), 6.57 (d, J=2.9 Hz, 1H),6.45 (d, J=2.9 Hz, 1H), 6.20 (d, J=2.1 Hz, 1H), 4.30 (d, J=4.3 Hz, 1H),3.70 (s, 3H), 3.53 (s, 3H), 2.28-2.09 (m, 1H), 0.80 (dd, J=11.7, 6.8 Hz,6H).

Example 10.2-isopropyl-6-methoxy-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 10 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compound ofExample 8. LCMS found (M+H)⁺: 382.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.02(s, 1H), 7.27 (d, J=4.5 Hz, 2H), 6.71 (d, J=2.7 Hz, 1H), 6.65 (d, J=2.7Hz, 1H), 6.19 (bs, 1H), 4.32 (d, J=4.7 Hz, 1H), 3.77 (s, 3H), 3.53 (s,3H), 3.31 (s, 3H), 2.22-2.10 (m, 1H), 0.77 (dd, J=15.1, 6.8 Hz, 6H).

Example 11.[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]aceticacid

Step 1. tert-butyl(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate

8-Bromo-2-isopropyl-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (0.15 g, 0.50mmol) of Example 10 was dissolved in N,N-dimethylformamide (2.0 mL, 26mmol) at room temperature under nitrogen. Sodium hydride in mineral oil(0.024 g, 0.60 mmol) was added and the reaction was stirred for 15minutes. Acetic acid, bromo-, 1,1-dimethylethyl ester (0.11 mL, 0.75mmol) was then added and the resulting mixture was stirred at roomtemperature for 1 h. The reaction mixture was then quenched with waterand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over magnesium sulfate, and concentrated toafford the crude product as a semisolid. The crude product was purifiedby FCC on silica gel eluting a hexane:ethyl acetate gradient to affordtert-butyl(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetateas a glass (0.15 g, 95%). LCMS calculated for C₁₈H₂₅BrNO₅ (M+H)⁺:m/z=414.1, 416.1; found=358.1, 360.1 (M+H-tButyl).

Step 2. tert-butyl(2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate

tert-Butyl(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate(0.030 g, 0.072 mmol) was combined with6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(0.031 g, 0.072 mmol) in 1,4-dioxane (1.8 mL) and potassium carbonate(0.022 g, 0.16 mmol) in water (0.61 mL). The mixture was degassed withnitrogen and the catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (0.006 g, 0.008 mmol) was added. The reactionmixture was heated in a sealed tube to 100° C. for 1 h. The reactionmixture was then cooled to room temperature and partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover magnesium sulfate, and concentrated to afford tert-butyl(2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetateas a dark oil (0.04g, 85%). LCMS calculated for C₃₃H₃₈N₃O₈S (M+H)⁺:m/z=636.2; found=636.2.

Step 3.[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]aceticacid

tert-Butyl(2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate(0.04g, 0.06 mmol) was dissolved in ethanol (3.7 mL) and 1.0 M sodiumhydroxide in water (1.2 mL). The mixture was heated to 80° C. in an oilbath for 1 h, allowed to cool to room temperature, and acidified withTFA. The product was purified by prep HPLC on a C-18 column eluting awater:acetonitrile gradient buffered at pH 2 with TFA, to afford thetitle product as an off white amorphous solid (0.02g, 65%). LCMScalculated for C₂₂H₂₄N₃O₆ (M+H)⁺: m/z=426.1; found=426.2. ¹H NMR (300MHz, DMSO-d₆) δ 13.02 (s, 1H), 12.03 (s, 1H), 7.37-7.21 (m, 2H), 6.66(d, J=2.7 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 6.20 (bs, 1H), 4.64 (s, 2H),4.34 (d, J=5.2 Hz, 1H), 3.74 (s, 3H), 3.54 (s, 3H), 2.13 (dd, J=12.3,6.5 Hz, 1H), 0.81 (d, J=6.9 Hz, 3H), 0.74 (d, J=6.7 Hz, 3H).

Example 12.2-[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-N-methylacetamide

Step 1.2-(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)aceticacid

tert-Butyl2-(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate(0.190 g, 0.459 mmol) of Example 11 was dissolved in methylene chloride(3.0 mL) and trifluoroacetic acid (1.0 mL) at room temperature for 2 h.The reaction mixture was concentrated in vacuo to afford crude2-(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)aceticacid (0.163 g, 100%) as an oil. LCMS calculated for C₁₄H₁₇BrNO₅ (M+H)⁺:m/z=358.1, 360.1; found=358.0, 360.0.

Step 2.2-(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide

2-(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)aceticacid (0.05 g, 0.1 mmol) was dissolved in N,N-dimethylformamide (2.0 mL),and 2.0 M methylamine in methanol (0.35 mL, 0.70 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.064 g, 0.17 mmol) (Oakwood cat #023926) wereadded. The reaction mixture was stirred at room temperature for 2 h andthen partitioned between ethyl acetate and water. The organic layer waswashed with 1 N HCl, brine, dried over magnesium sulfate, andconcentrated to afford crude2-(8-bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamideas a an oil (0.05 g, 100%). LCMS calculated for C₁₅H₂₀BrN₂O₄ (M+H)⁺:m/z=371.1, 373.1; found=371.0, 373.0.

Step 3.2-(2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide

2-(8-Bromo-2-isopropyl-6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide(0.027 g, 0.072 mmol) was combined with6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(0.031 g, 0.072 mmol) in 1,4-dioxane (1.8 mL) and potassium carbonate(0.022 g, 0.16 mmol) in water (0.61 mL). The mixture was degassed withnitrogen and the catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (0.006 g, 0.008 mmol) was added. The reactionmixture was then heated in a sealed tube to 100° C. for 1 h, cooled toroom temperature, and partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over magnesium sulfate, andconcentrated to afford crude2-(2-isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamideas a dark oil (0.035 g, 83%). LCMS calculated for C₃₀H₃₃N₄O₇S (M+H)⁺:m/z=593.1; found=593.2.

Step 4.2-[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-N-methylacetamide

2-(2-Isopropyl-6-methoxy-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide(0.035 g, 0.059 mmol) was dissolved in a mixture of ethanol (3.7 mL) and1.0 M sodium hydroxide in water (1.2 mL) and heated to 80° C. in an oilbath for 1 h. The mixture was then cooled to room temperature andacidified with TFA. The product was purified by prep HPLC on a C-18column eluting in a water: acetonitrile gradient buffered at pH 2 withTFA, to afford the title compound as an off white amorphous solid (0.015g, 47%). LCMS calculated for C₂₃H₂₇N₄O₅ (M+H)⁺: m/z=439.1; found=439.1.¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 8.09 (d, J=4.7 Hz, 1H), 7.27(d, J=2.6 Hz, 2H), 6.65 (d, J=2.7 Hz, 1H), 6.44 (d, J=2.7 Hz, 1H),6.23-6.14 (m, 1H), 4.58-4.38 (m, 2H), 4.35 (d, J=5.0 Hz, 1H), 3.72 (s,3H), 3.54 (s, 3H), 2.63 (d, J=4.5 Hz, 3H), 2.16 (dd, J=11.9, 6.9 Hz,1H), 0.81 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.7 Hz, 3H).

Examples 13-16

The compounds of Examples 13-16 and the experimental procedures used toprepare them are set out in Table 2 below.

TABLE 2

Ex. Synthetic No. Name R³ Procedure 13 2-[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-4-yl]acetamide

Ex. No. 12 14 2-isopropyl-6-methoxy-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-1,4- benzoxazin-3(4H)-one

Ex. No. 12 15 2-isopropyl-6-methoxy-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-4-(pyridin-4-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one

Ex. No. 8 16 2,4-diisopropyl-6-methoxy-8- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-2H-1,4-benzoxazin-3(4H)- one i-Prop Ex.No. 8

Example 17.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

Step 1. 3-bromo-4-hydroxy-5-nitrobenzonitrile

Bromine (500 mg, 3 mmol) was added to a mixture of4-hydroxy-3-nitrobenzonitrile (500 mg, 3 mmol) (Aldrich cat #344575),ferric chloride (100 mg, 0.9 mmol) and acetic acid (20 mL) at roomtemperature. The reaction mixture was heated to 50° C. for 2 h, allowedto cool to room temperature, and water (100 mL) was added. A precipitateslowly formed, was collected, washed with water, and dried to obtain3-bromo-4-hydroxy-5-nitrobenzonitrile (0.50 g, 70%) as a yellow solid.LCMS calculated for C₇H₄BrN₂O₃ (M+H)+: m/z=242.9, 244.9; found=242.9,244.9.

Step 2. 3-amino-5-bromo-4-hydroxybenzonitrile

Iron filings (300 mg, 5 mmol) were added to a mixture of3-bromo-4-hydroxy-5-nitrobenzonitrile (400 mg, 2 mmol) in acetic acid(20 mL). The mixture was then degassed with nitrogen and stirredovernight at room temperature. The reaction mixture was concentrated toremove the acetic acid, and the residue was partitioned between ethylacetate and aqueous saturated sodium bicarbonate. The combined organiclayers were washed with brine, dried over magnesium sulfate, filtered,and concentrated to afford crude 3-amino-5-bromo-4-hydroxybenzonitrileas a dark solid (250 mg, 70%). LCMS calculated for C₇H₆BrN₂O (M+H)⁺:m/z=212.9, 214.9; found=212.9, 214.9.

Step 3.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

Using methods similar to conditions in Example 9, but using3-amino-5-bromo-4-hydroxybenzonitrile, the title compound was preparedand purified by prep HPLC on a C-18 column eluting a water:acetonitrilegradient buffered at pH 2 with TFA to afford2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrileas a white amorphous solid (0.007 g, 40%). LCMS calculated forC₂₀H₁₉N₄O₃ (M+H)⁺: m/z=363.1; found=363.0. ¹H NMR (300 MHz, DMSO-d₆) δ12.06 (s, 1H), 11.01 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.34 (s, 1H), 7.27(t, J=2.7 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 6.24-6.13 (m, 1H), 4.62 (d,J=3.8 Hz, 1H), 3.53 (s, 3H), 2.29-2.16 (m, 1H), 0.78 (dd, J=6.8, 3.9 Hz,6H).

Example 18.2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

Step 1.8-bromo-2-isopropyl-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

Sodium hydride in mineral oil (2 mg, 0.07 mmol) was added to a mixtureof8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(20 mg, 0.07 mmol) of Example 17, in N,N-dimethylformamide (2 mL). Thereaction mixture was stirred for 5 minutes, methyl iodide (5.1 μL, 0.081mmol) was added, and the reaction mixture was stirred for an additional1 h. The reaction was then partitioned between ethyl acetate and water.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to afford crude8-bromo-2-isopropyl-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrileas a glass (0.020 g, 100%). LCMS calculated for C₁₃H₁₄BrN₂O₂ (M+H)⁺:m/z=309.1, 311.1; found=308.9, 310.7.

Step 2.2-isopropyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

8-Bromo-2-isopropyl-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(16 mg, 0.051 mmol) and6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(26 mg, 0.061 mmol) were dissolved in 1,4-dioxane (2 mL) with potassiumcarbonate (10 mg, 0.08 mmol) in water (0.9 mL) and the mixture wasdegassed with nitrogen. The catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (5 mg, 0.006 mmol) was added and the mixture washeated at 100° C. for 4 h. The reaction mixture was then cooled andpartitioned between water and ethyl acetate. The combined organic layerswere dried with MgSO₄ and concentrated to afford crude2-isopropyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile as aglass (0.027 g, 100%). LCMS calculated for C₂₈H₂₇N₄O₅S (M+H)⁺:m/z=531.1; found=531.2.

Step 3.2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

2-Isopropyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(0.027 g, 0.051 mmol) was dissolved in a mixture of ethanol (2 mL) and1.0 M sodium hydroxide in water (1 mL). The mixture was then heated at80° C. for 1 h. The reaction mixture was purified without workup by prepHPLC on a C-18 column eluting water: acetonitrile gradient buffered atpH 2 with TFA to afford the title compound as a white amorphous solid(0.005 g, 26%). LCMS calculated for C₂₁H₂₁N₄O₃ (M+H)⁺: m/z=377.1;found=377.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.65 (d, J=1.9Hz, 1H), 7.56 (d, 1H), 7.34 (s, 1H), 7.30-7.25 (m, 1H), 6.21-6.14 (m,1H), 4.62 (d, J=4.2 Hz, 1H), 3.54 (s, 3H), 3.34 (s, 3H), 2.27-2.18 (m,1H), 0.75 (d, J=6.8 Hz, 6H).

Example 19.2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

2-Isopropyl-4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrileof Example 18 was dissolved in a mixture of ethanol (2 mL) and 1.0 Msodium hydroxide in water (1 mL). The mixture was then heated at 80° C.for 4 h. The reaction mixture was purified without workup by prep HPLCon a C-18 column eluting a water: acetonitrile gradient buffered at pH 2with TFA to afford the title compound as a white amorphous solid(0.007g, 20%). LCMS calculated for C₂₁H₂₃N₄O₄ (M+H)⁺: m/z=395.1;found=395.2. ¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.00 (s, 1H),7.68 (d, J=1.3 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.35 (s, 1H), 7.30 (s,1H), 7.27 (t, J=2.5 Hz, 1H), 6.15 (t, J=2.1 Hz, 1H), 4.51 (d, J=4.3 Hz,1H), 3.55 (s, 3H), 3.36 (s, 3H), 2.21 (dd, J=11.4, 6.7 Hz, 1H), 0.77(dd, J=6.6 Hz, 6H).

Example 20.2-isopropyl-N-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

Step 1.8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylicacid

A solution of8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(from Example 18, 30 mg, 0.1 mmol) in concentrated hydrochloroic acid (1mL, 30 mmol) was heated at 100° C. for 10 h. The reaction mixture wascooled and concentrated in vacuo, then partitioned between water andethyl acetate. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated to afford crude8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylicacid as a solid residue (30 mg, 100%). LCMS calculated for C₁₂H₁₃BrNO₄(M+H)⁺: m/z=314.0, 316.0; found=313.9, 315.9.

Step 2.8-bromo-2-isopropyl-N-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (54 mg, 0.14 mmol) and N,N-diisopropylethylamine (30μL, 0.2 mmol) were added to a solution of8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylicacid (30 mg, 0.1 mmol) in DMF (2 mL). Methylamine in ethanol (3 M, 48μL, 0.14 mmol) was added and the reaction was stirred at roomtemperature for 1 h. The reaction mixture was then partitioned between 1N HCl and ethyl acetate. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated to afford crude8-bromo-2-isopropyl-N-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamideas a glass (30 mg, 90%). LCMS calculated for C₁₃H₁₆BrN₂O₃ (M+H)⁺:m/z=327.1, 329.1; found=327.0, 329.0.

Step 3.2-isopropyl-N-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

Using methods similar to conditions in Example 9, but using8-bromo-2-isopropyl-N-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamidefrom Step 2, the title compound was prepared and purified by prep HPLCon a C-18 column eluting a water: acetonitrile gradient buffered at pH 2with TFA to afford2-isopropyl-N-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamideas a white amorphous solid (5 mg, 30%). LCMS calculated for C₂₁H₂₃N₄O₄(M+H)⁺: m/z=395.1; found=395.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s,1H), 10.84 (s, 1H), 8.38-8.28 (m, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.37 (d,J=1.9 Hz, 1H), 7.28 (s, 1H), 7.27-7.23 (m, 1H), 6.18 (s, 1H), 4.49 (d,J=4.1 Hz, 1H), 3.55 (s, 3H), 2.73 (d, J=4.4 Hz, 3H), 2.27-2.14 (m, 1H),0.79 (dd, J=6.9, 2.0 Hz, 6H).

Example 21.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-nitro-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 21 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compound ofExample 9. LCMS found (M+H)⁺: 383.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11(s, 1H), 11.11 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.73 (d, J=2.8 Hz, 1H),7.36-7.22 (m, 2H), 6.23 (s, 1H), 4.70 (d, J=3.6 Hz, 1H), 3.55 (s, 3H),2.30-2.19 (m, 1H), 0.80 (d, J=6.8 Hz, 6H).

Example 22.4-(2-isopropyl-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-8-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Step 1. 8-bromo-2-isopropyl-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine

2.0 M Borane-dimethyl sulfide complex (Aldrich cat #194824) in toluene(400 μL, 0.7 mmol) was added dropwise to a mixture of8-bromo-2-isopropyl-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (100 mg, 0.4mmol) of Example 9 at room temperature and the mixture was then heatedat 60° C. overnight. The reaction mixture was cooled to roomtemperature, diluted with MeOH, and was heated at 60° C. for anadditional 30 min. The mixture was then cooled to room temperature andconcentrated to yield crude product. The crude product was purified byFCC on silica gel eluting a hexane:ethyl acetate gradient to afford8-bromo-2-isopropyl-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine as a clearoil (70 mg, 70%). LCMS calculated for C₁₂H₁₇BrNO₂ (M+H)⁺: m/z=286.1,288.1; found=286.0, 288.0.

Step 2.4-(2-isopropyl-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-8-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using methods similar to conditions in Example 8, but using8-bromo-2-isopropyl-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine from Step1, the title compound was prepared and purified by prep HPLC on a C-18column eluting a water: acetonitrile gradient buffered at pH 2 with TFAto afford4-(2-isopropyl-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-8-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneas a white amorphous solid (5 mg, 30%). LCMS calculated for C₂₁H₂₆N₃O₃(M+H)⁺: m/z=368.1; found=368.1. ¹H NMR (300 MHz, DMSO-d₆) δ 11.90 (s,1H), 7.21 (t, J=2.7 Hz, 1H), 7.16 (s, 1H), 6.24 (d, J=2.8 Hz, 1H), 6.18(d, J=2.8 Hz, 1H), 6.12 (d, J=2.1 Hz, 1H), 3.75-3.67 (m, 1H), 3.67 (s,3H), 3.51 (s, 3H), 3.30 (d, J=9.5 Hz, 1H), 3.01-2.91 (m, 1H), 2.85 (s,3H), 1.68-1.57 (m, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.7 Hz, 3H).

Examples 23-24

The compounds of Examples 23-24 and the experimental procedures used toprepare them are set out in Table 3 below.

TABLE 3

Ex. Synthetic No. Name R¹ Procedure 23 2-cyclopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)- one

Ex. No. 6 24 6-methoxy-8-(6-methyl-7- oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2- phenyl-2H-1,4-benzoxazin- 3(4H)-one

Ex. No. 6

Example 24A.6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 1) Example 24B.6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 2)

The enantiomers of Example 24 were separated by prep chiral HPLC usingthe following conditions: Column: Phenomenex Lux Cellulose C-4, 5 μm,21.2×25 mm; Mobile phase: 30% Ethanol in Hexanes; Gradient: 18 mL/min;Loading: 2 mg in 1800 μL; Run time: 28 min; Peak retention times: 20.9and 24.0 minutes.

Example 24A, Peak 1 (20.9 min) as a solid residue. LCMS calculated forC₂₃H₂₀N₃O₄ (M+H)⁺: m/z=402.1; found: 402.1. ¹H NMR (300 MHz, DMSO-d₆) δ11.93 (s, 1H), 10.90 (s, 1H), 7.28-7.17 (m, 4H), 7.13 (t, J=2.7 Hz, 1H),7.02 (s, 1H), 6.49 (d, J=2.9 Hz, 1H), 6.46 (d, J=2.9 Hz, 1H), 5.99 (s,1H), 5.61 (s, 1H), 3.65 (s, 3H), 3.42 (s, 3H).

Example 24B, Peak 2 (24.0 min) as a solid residue. LCMS calculated forC₂₃H₂₀N₃O₄ (M+H)⁺: m/z=402.1; found: 402.1. ¹H NMR (300 MHz, DMSO-d₆) δ11.93 (s, 1H), 10.90 (s, 1H), 7.28-7.17 (m, 4H), 7.13 (t, J=2.7 Hz, 1H),7.02 (s, 1H), 6.49 (d, J=2.9 Hz, 1H), 6.46 (d, J=2.9 Hz, 1H), 5.99 (s,1H), 5.61 (s, 1H), 3.65 (s, 3H), 3.42 (s, 3H).

Example 25.2-(2-chloro-4-fluorophenyl)-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. methyl bromo(2-chloro-4-fluorophenyl)acetate

A solution of methyl (2-chloro-4-fluorophenyl)acetate (100 mg, 0.5 mmol)(Acros Organics cat #30478) and N-bromosuccinimide (90 mg, 0.5 mmol) incarbon tetrachloride (0.7 mL) was heated to 100° C. for 1 h. Thereaction mixture was cooled to room temperature, filtered, andpartitioned between ethyl acetate and water. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated toafford crude methyl bromo(2-chloro-4-fluorophenyl)acetate as lightyellow semi solid (120 mg, 90%).

Step 2. 2-(2-chloro-4-fluorophenyl)-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using methylbromo(2-chloro-4-fluorophenyl)acetate from Step 1, the title compoundwas prepared and purified by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 2 with TFA to afford2-(2-chloro-4-fluorophenyl)-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-oneas a white amorphous solid (4 mg, 20%). LCMS calculated forC₂₃H₁₈ClFN₃O₄ (M+H)⁺: m/z=454.1; found=454.1. ¹H NMR (300 MHz, DMSO-d₆)δ 11.94 (s, 1H), 11.00 (s, 1H), 7.52-7.40 (m, 2H), 7.36-7.13 (m, 2H),7.11 (s, 1H), 6.55 (s, 1H), 6.13 (s, 1H), 5.87 (s, 1H), 3.74 (s, 3H),3.46 (s, 3H).

Example 26.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-1-{[2-(trimethylsilypethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, by using6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one(0.081 g, 0.20 mmol) (WO2013097601), the title compound was prepared asan oil. LCMS calculated for C₂₅H₃₅N₄O₅Si (M+H)⁺: m/z=499.2; found=499.2.

Step 2.2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

2-Isopropyl-6-methoxy-8-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-onewas dissolved in a mixture of methylene chloride and TFA (2:1) and wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated in vacuo to give an oily residue. This residue wasdissolved in ethanol (3 mL) and ammonium hydroxide (1 mL) and themixture was stirred overnight at room temperature. The mixture was thenconcentrated in vacuo to give a glassy residue. The product was purifiedby prep HPLC on a C-18 column eluting a water: acetonitrile gradientbuffered at pH 2 with TFA, to afford the title compound as an off whiteamorphous solid (25 mg, 42%). LCMS calculated for C₁₉H₂₁N₄O₄ (M+H)⁺:m/z=369.1; found=369.1. ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H), 7.80(s, 1H), 7.36 (s, 1H), 6.58 (d, J=2.4 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H),4.39 (d, J=3.8 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H), 2.28-2.11 (m, 1H),0.76 (dd, J=6.6, 3.4 Hz, 6H).

Example 27.6-methoxy-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 27 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compound ofExample 9 to give a white amorphous solid (15 mg, 25%). LCMS found(M+H)⁺: 354.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 10.59 (s, 1H),7.26 (t, J=2.7 Hz, 1H), 7.19 (s, 1H), 6.56 (d, J=2.9 Hz, 1H), 6.47 (d,J=2.9 Hz, 1H), 6.22-6.12 (m, 1H), 3.70 (s, 3H), 3.54 (s, 3H), 1.30 (s,6H).

Example 28.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. 4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenol

4-Bromo-2-nitrophenol (1.0 g, 4.6 mmol) (Aldrich cat #309877) wascombined with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.0 g, 5.0 mmol) (Acros Organics cat #38296) in 1,4-dioxane (20 mL) andcesium fluoride (1.5 g, 10 mmol) in water (10 mL). The mixture wasdegassed with nitrogen, the catalyst4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(0.1 g, 0.2 mmol) was added, and the mixture was heated in a sealed tubeto 100° C. for 1 h. The mixture was then cooled to room temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over magnesium sulfate, and concentrated toyield a dark oil. The product was purified by FCC on silica gel elutinga hexane:ethyl acetate gradient to afford4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenol as a yellow solid (0.20 g,20%). LCMS calculated for C₁₀H₁₀N₃O₃ (M+H)⁺: m/z=220.1; found =220.1.

Step 2. 2-bromo-4-(1-methyl-1H-pyrazol-4-yl)-6-nitrophenol

4-(1-Methyl-1H-pyrazol-4-yl)-2-nitrophenol (0.10 g, 0.46 mmol) wasdissolved in acetic acid (3.9 mL) and ferric chloride (0.01 g, 0.09mmol) in water (0.56 mL) was added. The reaction mixture was stirred atroom temperature followed by addition of bromine (0.073 g, 0.46 mmol) inacetic acid (2 mL). The resulting mixture was stirred for an additional2 h at room temperature then diluted with water to yield a slurry. Thisslurry was filtered and the solids were washed with water and dried. Theproduct was purified by FCC on silica gel eluting a hexane:ethyl acetategradient to afford 2-bromo-4-(1-methyl-1H-pyrazol-4-yl)-6-nitrophenol asa semisolid (0.12 g, 85%). LCMS calculated for C₁₀H₉BrN₃O₃ (M+H)⁺:m/z=298.1, 300.1; found=297.9, 299.9.

Step 3.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using2-bromo-4-(1-methyl-1H-pyrazol-4-yl)-6-nitrophenol from Step 2, thecrude product was prepared. The product was purified by prep HPLC on aC-18 column eluting a water: acetonitrile gradient buffered at pH 2 withTFA, to afford the title compound as an off white amorphous solid (18mg, 30%). LCMS calculated for C₂₃H₂₄N₅O₃ (M+H)⁺: m/z=418.2; found=418.2.¹H NMR (300 MHz, DMSO-d₆) δ 12.00 (s, 1H), 10.71 (s, 1H), 8.00 (s, 1H),7.68 (s, 1H), 7.29 (s, 1H), 7.28-7.23 (m, 1H), 7.17 (d, J=1.9 Hz, 1H),6.97 (d, J=1.9 Hz, 1H), 6.19 (s, 1H), 4.38 (d, J=4.2 Hz, 1H), 3.83 (s,3H), 3.55 (s, 3H), 2.29-2.11 (m, 1H), 0.87-0.73 (m, 6H).

Example 29.6-methoxy-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 29 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compounds ofExamples 9 and 26 to afford the title compound as an amorphous whitesolid (22 mg, 37%). LCMS found (M+H)⁺: 355.1. ¹H NMR (300 MHz, DMSO-d₆)δ 10.62 (s, 1H), 7.80 (s, 1H), 7.29 (s, 1H), 6.60 (d, J=2.9 Hz, 1H),6.49 (d, J=2.9 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H), 1.30 (s, 6H).

Example 30.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Step 1. methyl 1-(2-bromo-6-nitrophenoxy)cyclopropanecarboxylate

Sodium hydride in mineral oil (22 mg, 0.94 mmol) was added to a solutionof methyl 1-hydroxycyclopropanecarboxylate (40 mg, 0.4 mmol) (AcrosOrganics cat #30211) in tetrahydrofuran (2 mL). After 10 min 15-Crown-5(5 μL, 0.02 mmol) and 1-bromo-2-fluoro-3-nitrobenzene (100 mg, 0.4 mmol)(Ark Pharma cat #AK-35754) were added. The reaction mixture was stirredat room temperature overnight then quenched with methanol (1 mL) andpartitioned between ethyl acetate and water. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated toyield crude product. The product was purified by FCC on silica geleluting a hexane:ethyl acetate gradient to afford methyl1-(2-bromo-6-nitrophenoxy)cyclopropanecarboxylate as a semisolid (50 mg,40%). LCMS calculated for C₁₁H₁₁BrNO₅ (M+H)⁺: m/z=316.1, 318.1;found=315.9, 318.0.

Step 2. 8-bromospiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Iron powder (40 mg, 0.8 mmol) was added to a mixture of methyl1-(2-bromo-6-nitrophenoxy)cyclopropanecarboxylate (50 mg, 0.2 mmol) inacetic acid (20 mL) which was degassed with nitrogen. The reactionmixture was heated at 60° C. for 2 h and was subsequently concentratedto remove acetic acid. The resulting residue was partitioned betweenethyl acetate and aqueous saturated sodium bicarbonate. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford crude8-bromospiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one (40 mg, 100%).LCMS calculated for C₁₀H₉BrNO₂ (M+H)⁺: m/z=254.1, 256.1; found=253.9,256.0.

Step 3.8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

8-bromospiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one (13 mg, 0.050mmol) and6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(26 mg, 0.060 mmol) were dissolved in a mixture of 1-butanol (4 mL) andcesium fluoride (26 mg, 0.17 mmol) in water (1 mL). The reaction mixturewas then degassed with nitrogen and4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(20 mg, 0.02 mmol) was added. The resulting mixture was heated to 100°C. for 3 h. This mixture was then cooled to room temperature and betweenethyl acetate and water. The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated to yield crude product. Theproduct was purified by FCC on silica gel eluting a hexane: ethylacetate gradient to afford8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-oneas a semisolid (20 mg, 63%). LCMS calculated for C₂₅H₂₂N₃O₅S (M+H)⁺:m/z=476.1; found=476.1.

Step 4.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl[spiro1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

8-{6-Methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-onewas dissolved in a mixture of ethanol (4 mL) and 1.0 M sodium hydroxidein water (2 mL) and the resulting mixture was heated at 80° C. for 1 h.The reaction mixture was then concentrated and partitioned between ethylacetate and water. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated to yield crude product. Theproduct was purified by prep HPLC on a C-18 column eluting awater:acetonitrile gradient buffered at pH 2 with TFA, to afford thetitle compound as an off white amorphous solid (7 mg, 40%). LCMScalculated for C₁₈H₁₆N₃O₃ (M+H)⁺: m/z=322.1; found=322.1 ¹H NMR (300MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.82 (s, 1H), 7.25 (t, J=2.7 Hz, 1H),7.12 (s, 1H), 7.07-6.95 (m, 2H), 6.91 (dd, J=7.3, 2.0 Hz, 1H), 6.09 (t,J=2.2 Hz, 1H), 3.51 (s, 3H), 1.25-1.14 (m, 2H), 1.09-0.99 (m, 2H).

Example 31.2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 31 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compound ofExample 1 to afford the title compound as an amorphous white solid (15mg, 25%). LCMS found (M+H)⁺: 324.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.02(s, 1H), 10.66 (s, 1H), 7.26 (t, J=2.7 Hz, 1H), 7.17 (s, 1H), 7.00 (s,1H), 6.99 (d, J=2.1 Hz, 1H), 6.88 (dd, J=5.7, 3.6 Hz, 1H), 6.13 (s, 1H),3.54 (s, 3H), 1.33 (s, 6H).

Example 32.3,3-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one

Step 1. methyl 2-[(2-bromo-6-nitrophenyl)amino]-2-methylpropanoate

Sodium bicarbonate (70 mg, 0.83 mmol) was added to a solution of1-bromo-2-fluoro-3-nitrobenzene (100 mg, 0.4 mmol) and methyl2-amino-2-methylpropanoate hydrochloride (90 mg, 0.6 mmol) (Aldrich cat#A8754) in N-methylpyrrolidinone (1 mL) and the resulting solution washeated to 100° C. overnight. The reaction mixture was then cooled toroom temperature and was partitioned between ethyl acetate and water.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to yield a crude residue. The product waspurified by FCC on silica gel eluting a hexane:ethyl acetate gradient toafford methyl 2-[(2-bromo-6-nitrophenyl)amino]-2-methylpropanoate as asemi-solid (50 mg, 30%). LCMS calculated for C₁₁H₁₄BrN₂O₄ (M+H)⁺:m/z=317.1, 319.1; found=317.0, 319.0.

Step 2.3,3-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroquinoxahn-2(1H)-one

Using methods similar to conditions in Example 30, but using methyl2-[(2-bromo-6-nitrophenyl)amino]-2-methylpropanoate from Step 1, thecrude product was prepared. The product was purified by prep HPLC on aC-18 column eluting a water : acetonitrile gradient buffered at pH 2with TFA, to afford the title compound as an off white amorphous solid(4 mg, 20%). LCMS calculated for C₁₈H₁₉N₄O₂ (M+H)⁺: m/z=323.1;found=323.1.

Examples 33-34

The compounds of Examples 33-34 and the experimental procedures used toprepare them are set out in Table 4 below.

TABLE 4

Ex. Synthetic No. Name R⁵ Procedure 33 2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridin-4-yl)-6-(morpholin-4-ylcarbonyl)-2H- 1,4-benzoxazin-3(4H)-one

20 34 2-isopropyl-N,N-dimethyl-8- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

20

Example 35.2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. ethyl bromo(cyclopentyl)acetate

Thionyl chloride (0.35 mL, 4.8 mmol) was added dropwise to a solution ofcyclopentaneacetic acid (0.5 g, 4 mmol) (Alfa Aesar cat #A15696) in1,2-dichloroethane (20 mL) at room temperature. The reaction mixture washeated to reflux for 2 h then cooled to room temperature, at which timeN-bromosuccinimide (850 mg, 4.8 mmol) and hydrogen bromide (5 μL, 0.09mmol) (48% aqueous solution) were added successively. This mixture wasthen heated to reflux for 2 days. The mixture was then cooled to roomtemperature, ethanol (5 mL, 80 mmol) was added, and the resultingmixture was stirred for an additional 2 h at room temperature. Thereaction mixture was then concentrated to give a crude residue. Thisresidue was suspended in carbon tetrachloride, passed through a shortpad of silica gel, and concentrated to afford crude ethylbromo(cyclopentyl)acetate as an oil (0.8 g, 90%). LCMS calculated forC₉H₁₆BrO₂ (M+H)⁺: m/z=235.1; found=235.1 .

Step 2.2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using ethylbromo(cyclopentyl)acetate from Step 1, the crude product was prepared.The product was purified by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 2 with TFA to afford the titlecompound as an off white amorphous solid (8 mg, 40%). LCMS calculatedfor C₂₂H₂₄N₃O₄ (M+H)⁺: m/z=394.1; found=394.2. ¹H NMR (500 MHz, DMSO-d₆)δ 11.99 (s, 1H), 10.56 (s, 1H), 7.27 (s, 2H), 6.58 (d, J=2.9 Hz, 1H),6.47 (d, J=2.9 Hz, 1H), 6.20 (s, 1H), 4.36 (d, J=6.1 Hz, 1H), 3.71 (s,3H), 3.54 (s, 3H), 2.39-2.29 (m, 1H), 1.63-1.18 (m, 8H).

Example 35A.2-Cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 1) Example 35B.2-Cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 2)

The enantiomers of compound Example 35 were separated by Chiral columnHPLC using the following conditions: Column: Phenomenex Lux CelluloseC-4, 5 μm, 21.2×250 mm; Mobile phase: 60% Ethanol in Hexane; Gradient:18 mL/min isocratic; Loading: 1 mg in 900 μL; Run time: 11 min;Retention times: 7.7 and 8.7 minutes.

Example 35A, Peak 1 (7.7 min). LCMS calculated for C₂₂H₂₄N₃O₄ (M+H)⁺:m/z=394.1; found=394.2. ¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (s, 1H), 10.56(s, 1H), 7.27 (s, 2H), 6.58 (d, J=2.9 Hz, 1H), 6.47 (d, J=2.9 Hz, 1H),6.20 (s, 1H), 4.36 (d, J=6.1 Hz, 1H), 3.71 (s, 3H), 3.54 (s, 3H),2.39-2.29 (m, 1H), 1.63-1.18 (m, 8H).

Example 35B, Peak 2 (8.7 minutes). LCMS calculated for C₂₂H₂₄N₃O₄(M+H)⁺: m/z=394.1; found=394.2. ¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (s,1H), 10.56 (s, 1H), 7.27 (s, 2H), 6.58 (d, J=2.9 Hz, 1H), 6.47 (d, J=2.9Hz, 1H), 6.20 (s, 1H), 4.36 (d, J=6.1 Hz, 1H), 3.71 (s, 3H), 3.54 (s,3H), 2.39-2.29 (m, 1H), 1.63-1.18 (m, 8H).

Example 36.6-(hydroxymethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1.8-bromo-6-(hydroxymethyl)-2-isopropyl-2H-1,4-benzoxazin-3(4H)-one

Isobutyl chloroformate (50 μL, 0.38 mmol) was added dropwise to asolution of8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylicacid (from Example 20, 100 mg, 0.3 mmol) in tetrahydrofuran (10 mL) andtriethylamine (53 μL, 0.38 mmol) cooled to 0° C. The resulting mixturewas stirred for 2 h then added to a stirred solution of sodiumtetrahydroborate (40 mg, 1 mmol) in water (4 mL) at 0° C. This mixturewas warmed to room temperature and stirred for an additional 18 h. Themixture was then acidified using 1 N HCl and partitioned between ethylacetate and water. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated to yield crude product. Theproduct was purified by FCC on silica gel eluting a hexane: ethylacetate gradient to afford8-bromo-6-(hydroxymethyl)-2-isopropyl-2H-1,4-benzoxazin-3(4H)-one as asemisolid (80 mg, 80%). LCMS calculated for C₁₂H₁₅BrNO₃ (M+H)⁺:m/z=300.1, 302.1; found=300.0, 302.1.

Step 2.6-(hydroxymethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using8-bromo-6-(hydroxymethyl)-2-isopropyl-2H-1,4-benzoxazin-3(4H)-one ofStep 1, the crude product was prepared. The product was purified by prepHPLC on a C-18 column eluting a water:acetonitrile gradient buffered atpH 2 with TFA, to afford the title compound as an off white amorphoussolid (50 mg, 70%). LCMS calculated for C₂₀H₂₂N₃O₄ (M+H)⁺: m/z=368.1;found=368.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.69 (s, 1H),7.32-7.22 (m, 2H), 6.95 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H),6.24-6.15 (m, 1H), 4.45 (d, J=4.2 Hz, 1H), 4.42 (s, 2H), 3.53 (s, 3H),2.29-2.11 (m, 1H), 0.89-0.72 (m, 6H).

Example 37.2-isopropyl-6-(methoxymethyl)-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1.8-bromo-2-isopropyl-6-(methoxymethyl)-2H-1,4-benzoxazin-3(4H)-one

A solution of8-bromo-6-(hydroxymethyl)-2-isopropyl-2H-1,4-benzoxazin-3(4H)-one (20mg, 0.07 mmol) of Example 36 in methanol (2 mL, 50 mmol) was treatedwith p-toluenesulfonic acid monohydrate (10 mg, 0.07 mmol) and theresulting mixture was heated in a microwave at 90° C. for 40 min. Thismixture was cooled to room temperature, concentrated, and partitionedbetween ethyl acetate and water. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated to afford8-bromo-2-isopropyl-6-(methoxymethyl)-2H-1,4-benzoxazin-3(4H)-one as aclear oil (20 mg, 100%). LCMS calculated for C₁₃H₁₇BrNO₃ (M+H)⁺:m/z=314.1, 316.1; found=314.0, 316.1.

Step 2.2-isopropyl-6-(methoxymethyl)-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using8-bromo-2-isopropyl-6-(methoxymethyl)-2H-1,4-benzoxazin-3(4H)-one fromStep 1, the crude product was prepared. The product was purified by prepHPLC on a C-18 column eluting a water: acetonitrile gradient buffered atpH 2 with TFA to afford the title compound as an off white amorphoussolid (6 mg, 30%). LCMS calculated for C₂₁H₂₄N₃O₄ (M+H)⁺: m/z=382.1;found=382.1. ¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (s, 1H), 10.69 (s, 1H),7.30-7.23 (m, 2H), 6.96 (d, J=1.8 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.18(t, J=2.3 Hz, 1H), 4.39 (d, J=4.2 Hz, 1H), 4.34 (s, 2H), 3.54 (s, 3H),3.28 (s, 3H), 2.25-2.17 (m, 1H), 0.82 (dd, J=15.5, 6.8 Hz, 6H).

Example 38.6-(Aminomethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. tert-butyl[(8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]carbamate

To an ice-cooled solution of8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(from Example 17, 100 mg, 0.3 mmol) in methanol (5 mL) was addeddi-tert-butyldicarbonate (100 mg, 0.7 mmol) and nickel chloridehexahydrate (8 mg, 0.03 mmol), followed by portion-wise addition ofsodium tetrahydroborate (90 mg, 2 mmol). The resulting black solutionwas stirred at 0° C. for 30 min then warmed to room temperature andstirred overnight. N¹-(2-aminoethyl)ethane-1,2-diamine (10 mg, 0.1 mmol)was then added, and the mixture was concentrated to dryness. Theresulting residue was dissolved in ethyl acetate and washed with 10%citric acid followed by saturated sodium bicarbonate. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to yield crude product. The product was purified by FCC onsilica gel eluting a hexane: ethyl acetate gradient to afford tert-butyl[(8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]carbamateas a semi-solid (100 mg, 70%). LCMS calculated for C₁₇H₂₃BrN₂O₄ (M+H)⁺:m/z=399.1, 401.1; found=399.1, 401.0.

Step 2.6-(aminomethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using tert-butyl[(8-bromo-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]carbamatefrom Step 1, the crude product was prepared. The product was purified byprep HPLC on a C-18 column eluting a water:acetonitrile gradientbuffered at pH 10 to afford the title compound as an off white amorphoussolid (5 mg, 50%). LCMS calculated for C₂₀H₂₃N₄O₃ (M+H)⁺: m/z=367.1;found=367.2.

Example 39.N-{[2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]methyl}ethanesulfonamide

Step 1.6-(aminomethyl)-2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-onehydrochloride

tert-Butyl[(2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]carbamate(100 mg, 0.2 mmol) of Example 38 was dissolved in 4 M hydrogen chloridein dioxane (5 mL) at room temperature and the mixture was stirred for 2h. The reaction was then concentrated to afford crude6-(aminomethyl)-2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-onehydrochloride as a white salt (100 mg, 100%). LCMS calculated forC₂₇H₂₉N₄O₅S (M+H)⁺: m/z=521.1; found=521.2.

Step 2.N-[(2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]ethanesulfonamide

Ethanesulfonyl chloride (4.1 mg, 0.032 mmol) was added to a solution of6-(aminomethyl)-2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-onehydrochloride (16 mg, 0.029 mmol) in methylene chloride (1.0 mL) andtriethylamine (8 μL, 0.06 mmol) at 0° C. and the mixture was stirred at0° C. for 30 min. The mixture was partitioned between ethyl acetate andwater. The organic layer was then washed with brine, dried over MgSO₄,filtered, and concentrated to afford crudeN-[(2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]ethanesulfonamideas a semisolid (15 mg, 85%). LCMS calculated for C₂₉H₃₃N₄O₇S₂ (M+H)⁺:m/z=613.1; found=613.2.

Step 3.N-{[2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]methyl}ethanesulfonamide

Using methods similar to conditions in Example 9, but usingN-[(2-isopropyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]ethanesulfonamidefrom Step 2, the crude product was prepared. The product was purified byprep HPLC on a C-18 column eluting a water:acetonitrile gradientbuffered at pH 10 to afford the title compound as an off white amorphoussolid (6 mg, 40%). LCMS calculated for C₂₂H₂₇N₄O₅S (M+H)⁺: m/z=459.1.1;found=459.2. ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 10.74 (s, 1H),7.57 (t, J=6.2 Hz, 1H), 7.32-7.26 (m, 1H), 7.25 (s, 1H), 7.01 (d, J=1.9Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 6.23 (d, J=2.5 Hz, 1H), 4.37 (d, J=4.3Hz, 1H), 4.06 (d, J=6.2 Hz, 2H), 3.54 (s, 3H), 2.94 (q, J=7.3 Hz, 2H),2.29-2.12 (m, 1H), 1.16 (t, J=7.4 Hz, 3H), 0.81 (dd, J=14.0, 6.8 Hz,6H).

Examples 40-41

The compounds of Examples 40-41 and the experimental procedures used toprepare them are set out in Table 5 below.

TABLE 5

Ex. Synthetic No. Name R⁵ Procedure 40 N-{[2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4- benzoxazin-6-yl]methyl} acetamide

Ex. No. 39 41 2-isopropyl-8-(6-methyl-7- oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3- oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

Ex. No. 20

Example 42.2-Cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 42 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compounds ofExamples 35 and 26 to afford the title compound as an amorphous whitesolid (50 mg, 50%). LCMS found (M+H)⁺=395.2. ¹H NMR (300 MHz, DMSO-d₆) δ10.61 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 6.59 (d, J=2.9 Hz, 1H), 6.49(d, 1H), 4.44 (d, J=5.9 Hz, 1H), 3.72 (s, 3H), 3.26 (s, 3H), 2.39-2.23(m, 1H), 1.59-1.19 (m, 8H).

Example 42A.2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 1) Example 42B.2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 2)

Step 1.2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 42, the intermediateproduct2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-onewas prepared as a pair of enantiomers. The enantiomers were separated bychiral column HPLC using the following conditions: Column: PhenomenexLux Cellulose C-4, 5 μm, 21.2×250 mm; Mobile phase: 60% Ethanol inHexane; Gradient: 18 mL/min isocratic; Loading: 1 mg in 900 μL; Runtime: 7 min.; Retention time: 2.9 and 5.0 minutes.

Intermediate Peak 1 (2.9 minutes). LCMS calculated for C₂₇H₃₇N₄O₅Si(M+H)⁺: m/z=525.1; found=525.2.

Intermediate Peak 2 (5.0 minutes). LCMS calculated for C₂₇H₃₇N₄O₅Si(M+H)⁺: m/z=525.1; found=525.2.

Step 2.2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 42, but using thepurified enantiomers of Step 1, the crude product was prepared. Theproduct was purified by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 10, to afford the title compound asan off white amorphous solid.

Example 42A. Peak 1. LCMS calculated for C₂₁H₂₃N₄O₄ (M+H)⁺: m/z=395.1;found=395.1. ¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.80 (s, 1H),7.35 (s, 1H), 6.59 (d, J=2.9 Hz, 1H), 6.49 (d, 1H), 4.44 (d, J 5.9 Hz,1H), 3.72 (s, 3H), 3.26 (s, 3H), 2.39-2.23 (m, 1H), 1.59 — 1.19 (m, 8H).

Example 42B. Peak 2. LCMS calculated for C₂₁H₂₃N₄O₄ (M+H)⁺: m/z=395.1;found=395.1. ¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.80 (s, 1H),7.35 (s, 1H), 6.59 (d, J=2.9 Hz, 1H), 6.49 (d, 1H), 4.44 (d, J=5.9 Hz,1H), 3.72 (s, 3H), 3.26 (s, 3H), 2.39-2.23 (m, 1H), 1.59 — 1.19 (m, 8H).

Example 43.6-(2-furyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 43 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compound ofExample 28 to afford the title compound as an amorphous white solid (15mg, 25%). LCMS found (M+H)⁺=404.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.22 (s,1H), 10.76 (s, 1H), 7.74 (s, 1H), 7.42-7.36 (m, 1H), 7.31 (d, J=20.1 Hz,2H), 7.02 (d, J=8.3 Hz, 1H), 6.85 (s, 2H), 6.77 (s, 1H), 4.38 (d, J=5.4Hz, 1H), 3.59 (s, 3H), 2.24-2.10 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.94(d, J=6.7 Hz, 3H).

Example 44.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

Step 1.2-[2-hydroxy-5-(methylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dione

Phthalic anhydride (1.7 g, 12 mmol) was added to a solution of2-amino-4-(methylsulfonyl)phenol (2.0 g, 11 mmol) (TCI cat #A2198) inacetic acid (40.0 mL) and the resulting mixture was heated to 120° C.for 18 h. The reaction was then cooled to room temperature and pouredover water (150 mL), where it slowly formed a precipitate. The solidswere collected and dried to afford2-[2-hydroxy-5-(methylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dione as atan crystalline solid (3.0 gm, 80%). LCMS calculated for C₁₅H₁₂NO₅S(M+H)⁺: m/z=318.1; found=318.0.

Step 2.2-[3-bromo-2-hydroxy-5-(methylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dione

Bromine (0.52 mL, 10 mmol) in acetic acid (2 mL) was slowly added to asolution of2-[2-hydroxy-5-(methylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dione (3.2g, 10. mmol) in acetic acid (160 mL) and ferric chloride (0.3 g, 2 mmol)in water (32 mL) at room temperature. The reaction mixture was stirredfor 2 h and then diluted with water to yield a slurry. The solids werefiltered off, washed with water, and dried to afford2-[3-bromo-2-hydroxy-5-(methylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dioneas an off white powder (3.1 g, 78%). LCMS calculated for C₁₅H₁₁BrNO₅S(M+H)⁺: m/z=396.1, 398.1; found=396.0, 398.0.

Step 3. 2-amino-6-bromo-4-(methylsulfonyl)phenol

Hydrazine (0.48 mL, 15 mmol) was added to a solution of2-[3-bromo-2-hydroxy-5-(methylsulfonyl)phenyl]-1H-isoindole-1,3(2H)-dione(3.0 g, 7.6 mmol) in ethanol (150 mL) at room temperature. The reactionwas stirred at room temperature for 15 minutes, forming a slurry. Themixture was then heated to 100° C. for 18 h, cooled to room temperature,filtered, and the mother liquor was concentrated in vacuo to yieldsemisolid residue. This residue was suspended in ethyl acetate,filtered, and concentrated to afford2-amino-6-bromo-4-(methylsulfonyl)phenol as a viscous oil (1.8 g, 90%).LCMS calculated for C₇H₉BrNO₃S (M+H)⁺: m/z=266.1, 268.1; found=265.9,267.9.

Step 4.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using2-amino-6-bromo-4-(methylsulfonyl)phenol from Step 1, the crude productwas prepared. The product was purified by prep HPLC on a C-18 columneluting a water: acetonitrile gradient buffered at pH 10 to afford thetitle compound as an off white amorphous solid (55 mg, 68%). LCMScalculated for C₂₀H₂₂N₃O₅S (M+H)⁺: m/z=416.1; found=416.1. ¹H NMR (300MHz, DMSO-d₆) δ 12.09 (s, 1H), 11.03 (s, 1H), 7.55 (d, J=2.2 Hz, 1H),7.38 (s, 2H), 7.29 (t, J=2.6 Hz, 1H), 6.21 (s, 1H), 4.62 (d, J=3.9 Hz,1H), 3.55 (s, 3H), 3.20 (s, 3H), 2.32-2.18 (m, 1H), 0.80 (d, J=6.7 Hz,6H).

Example 44A.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-oneExample 44B.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

The enantiomers of compound Example 44 were separated by prep chiralcolumn chromatography using the following conditions: Column: phenomenexLux Cellulose C-4, 5 μm, 21, 2×250 mm; Mobile phase: 80% EtOH/Hexanes;Gradient condition: isocratic at 18 mL/min; Loading: 1.5 mg in 900 μL;Run time: 17 min; Peak retention times: 11.6 and 14.8 min.

Example 44A. Peak 1 (11.6 min) as a solid residue. LCMS calculated forC₂₀H₂₂N₃O₅S (M+H)⁺: m/z=416.1; found=416.1. ¹H NMR (300 MHz, DMSO-d₆) δ12.09 (s, 1H), 11.03 (s, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.38 (s, 2H), 7.29(t, J=2.6 Hz, 1H), 6.21 (s, 1H), 4.62 (d, J=3.9 Hz, 1H), 3.55 (s, 3H),3.20 (s, 3H), 2.32-2.18 (m, 1H), 0.80 (d, J=6.7 Hz, 6H).

Example 44B. Peak 2 (14.8 min) as a solid residue. LCMS calculated forC₂₀H₂₂N₃O₅S (M+H)⁺: m/z=416.1; found=416.1. ¹H NMR (300 MHz, DMSO-d₆) δ12.09 (s, 1H), 11.03 (s, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.38 (s, 2H), 7.29(t, J=2.6 Hz, 1H), 6.21 (s, 1H), 4.62 (d, J=3.9 Hz, 1H), 3.55 (s, 3H),3.20 (s, 3H), 2.32-2.18 (m, 1H), 0.80 (d, J=6.7 Hz, 6H).

Examples 45-47

The compounds of Examples 45-47 and the experimental procedures used toprepare them are set out in Table 6 below.

TABLE 6

Ex. Synthetic No. Name R¹ R² R³ Procedure 452,2-dimethyl-8-(6-methyl-7-oxo- CH₃— CH₃— H 446,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one 46 8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)- 6-(methylsulfonyl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one

H H 44 47 2-isopropyl-4-methyl-8- i-Prop H Me 44, 8(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4- benzoxazin-3(4H)-one

Example 47A.2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-oneExample 47B.2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

The enantiomers of compound Example 47 were separated by prep chiralcolumn chromatography using the following conditions: Column: ChiralpakIA, 5 μm, 21, 2×250 mm; Mobile phase: 80% EtOH/Hexanes; Gradientcondition: isocratic at 8 mL/min; Loading: 16.0 mg in 900 μL; Run time:70 min; Peak retention times: 27.3 and 51.3 min.

Example 47A, Peak 1 (27.3 min). LCMS calculated for C₂₁H₂₄N₃O₅S (M+H)⁺:m/z=430.1; found=430.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.58(d, J=2.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J=2.8Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.59 (d, J=4.2 Hz, 1H), 3.51 (s, 3H),3.34 (s, 3H), 3.23 (s, 3H), 2.25-2.13 (m, 1H), 0.73 (dd, J=6.7, 4.8 Hz,6H).

Example 47B, Peak 2 (51.3 min). LCMS calculated for C₂₁H₂₄N₃O₅S (M+H)⁺:m/z=430.1; found=430.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.58(d, J=2.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J=2.8Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.59 (d, J=4.2 Hz, 1H), 3.51 (s, 3H),3.34 (s, 3H), 3.23 (s, 3H), 2.25-2.13 (m, 1H), 0.73 (dd, J=6.7, 4.8 Hz,6H).

Examples 48-49

The compounds of Examples 48-49 and the experimental procedures used toprepare them are set out in Table 7 below.

TABLE 7

Ex. Synthetic No. Name R¹ R⁵ Procedure 48 2-(2-hydroxyethyl)-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H- 1,4-benzoxazin-3(4H)-one

Ex. No. 44 49 6-acetyl-2-isopropyl-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-2H-1,4-benzoxazin-3(4H)- one i-Prop

Ex. No. 9

Example 50.6-(1-hydroxyethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

6-Acetyl-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(from Example 49, 0.050 g, 0.13 mmol) was dissolved in methanol (5.0 mL)at room temperature and sodium tetrahydroborate (0.010 g, 0.26 mmol) wasadded. The reaction mixture was stirred for 1 h and the product waspurified without workup by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 10 to afford the title compound asa white amorphous solid (25 mg, 50%). LCMS calculated for C₂₁H₂₄N₃O₄(M+H)⁺: m/z=382.1; found: 382.2. ¹H NMR (300 MHz, DMSO-d₆) δ 11.96 (s,1H), 10.61 (s, 1H), 7.25-7.13 (m, 2H), 6.93 (dd, J=5.3, 1.9 Hz, 1H),6.82 (dd, J=5.8, 1.9 Hz, 1H), 6.14 (s, 1H), 5.09 (d, J=3.9 Hz, 1H),4.68-4.52 (m, 1H), 4.30 (d, J=3.7 Hz, 1H), 3.49 (s, 3H), 2.23-2.05 (m,1H), 1.25 (d, J=6.3 Hz, 3H), 0.76 (dd, J=12.5, 6.8 Hz, 6H).

Example 51.6-(ethylsulfonyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. 4-(ethylthio)phenol

4-Mercaptophenol (0.5 g, 4 mmol) (Aldrich cat #559938-5) was dissolvedin acetone (10.0 mL) and potassium carbonate (0.684 g, 4.95 mmol) andiodoethane (0.396 mL, 4.95 mmol) were added. The reaction mixture wasstirred at room temperature for 2 h, diluted with ethyl acetate, andfiltered. The organic layer was concentrated in vacuo to yield a yellowoil. The product was purified by FCC on silica gel eluting ahexane:ethyl acetate gradient to afford 4-(ethylthio)phenol as a clearoil which crystallized upon sitting (0.5 g, 80%).

Step 2. 4-(ethylsulfonyl)phenol

Oxone (0.99 g, 6.5 mmol) (Aldrich cat #22803-6) was added in portions toa solution of 4-(ethylthio)phenol(0.50 g, 3.2 mmol) in ethanol (10.0 mL)and water (10.0 mL) at room temperature. The reaction mixture wasstirred for 18 h then partitioned between ethyl acetate and water. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, and concentrated in vacuo to afford 4-(ethylsulfonyl)phenol asa semisolid (0.58 g, 96%). LCMS calculated for C₈H₁₁O₃S (M+H)⁺:m/z=187.0; found: 187.0.

Step 3. 4-(ethylsulfonyl)-2-nitrophenol

Nitric acid (0.1 mL, 3 mmol) was added to a mixture of4-(ethylsulfonyl)phenol (0.5 g, 3 mmol) in acetic acid (9 mL) at roomtemperature. The mixture was heated to 80° C. for 3 h then cooled toroom temperature and partitioned between ethyl acetate and water. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to yield crude product. The product wascrystallized from ethyl ether to afford 4-(ethylsulfonyl)-2-nitrophenolas a pale yellow solid (0.59 g, 100%). LCMS calculated for C₈H₁₀NO₅S(M+H)⁺: m/z=232.1; found: 232.0.

Step 4. 2-bromo-4-(ethylsulfonyl)-6-nitrophenol

Bromine (0.41 g, 2.6 mmol) in acetic acid (5 mL) was added to a solutionof 4-(ethylsulfonyl)-2-nitrophenol (0.6 g, 2 mmol) in acetic acid (20mL) and ferric chloride (0.08 g, 0.5 mmol) in water (0.3 mL) at roomtemperature and the resulting mixture was stirred for 4 h. This mixturewas then diluted with water (70 mL), forming a slurry. The solids werecollected, washed with water, and dried to afford2-bromo-4-(ethylsulfonyl)-6-nitrophenol as an off white powder (0.72 gm,80%). LCMS calculated for C₈H₉BrNO₅ (M+H)⁺: m/z=310.0, 312.0; found:310.0, 311.9.

Step 5. 2-amino-6-bromo-4-(ethylsulfonyl)phenol

2-Bromo-4-(ethylsulfonyl)-6-nitrophenol (0.20 g, 0.64 mmol) wasdissolved in ethanol (7.0 mL, 120 mmol), degassed with nitrogen, andRaney Nickel (75 mg) was added. The reaction mixture was stirred under ahydrogen atmosphere for 2 h. The mixture was decanted from the solidsand concentrated in vacuo to afford2-amino-6-bromo-4-(ethylsulfonyl)phenol as a glass (0.11 g, 47%). LCMScalculated for C₈H₁₁BrNO₃S (M+H)⁺: m/z=280.1, 282.1; found: 280.0,282.0.

Step 6.6-(ethylsulfonyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 44, but using2-amino-6-bromo-4-(ethylsulfonyl)phenol from Step 5, the crude productwas prepared. The product was purified by prep HPLC on a C-18 columneluting a water: acetonitrile gradient buffered at pH 10 to afford thetitle compound as an off white amorphous solid (25 mg, 20%). LCMScalculated for C₂₁H₂₄N₃O₅S (M+H)⁺: m/z=430.1; found 430.2. ¹H NMR (300MHz, DMSO-d₆) δ 12.05 (s, 1H), 10.95 (bs, 1H), 7.43 (d, J=2.2 Hz, 1H),7.33 (s, 1H), 7.27 (dd, J=10.2, 2.4 Hz, 2H), 6.14 (d, J=2.7 Hz, 1H),4.57 (d, J=3.8 Hz, 1H), 3.50 (s, 3H), 3.21 (q, 2H), 2.28-2.12 (m, 1H),1.07 (t, J=7.3 Hz, 3H), 0.76 (d, J=6.7 Hz, 6H).

Examples 52-56

The compounds of Examples 52-56 and the experimental procedures used toprepare them are set out in Table 8 below.

TABLE 8

Ex. Synthetic No. Name R³ R⁵ Procedure 52 2-isopropyl-6-(isopropylsulfonyl)-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-2H-1,4-benzoxazin-3(4H)- one H

44 53 4-(cyclopropylmethyl)-2- isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

44, 8 54 4-ethyl-2-isopropyl-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one Et

44, 8 55 6-(ethylsulfonyl)-2-isopropyl- 4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4-benzoxazin- 3(4H)-oneMe

44, 8 56 2-isopropyl-6- (isopropylsulfonyl)-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one Me

44, 8

Example 57.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Step 1. 1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene

Bromine (1 g, 9 mmol) was added dropwise to a solution of1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (2 g, 9 mmol) (Oakwood cat#009288) in sulfuric acid (10 mL), followed by dropwise addition ofnitric acid (0.42 mL, 10. mmol). The resulting mixture was heated to 80°C. for 5 h then cooled and poured over ice. The aqueous layer wasextracted with methylene chloride and the combined organic layers werewashed with saturated Na₂S₂O₃, brine, dried over MgSO₄, filtered, andconcentrated to yield crude material. The product was purified by FCC onsilica gel eluting a hexane: ethyl acetate gradient to afford1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene as a glass (0.80 g,30%). LCMS calculated for C₇H₆BrNO₄S (M+H)⁺: m/z=298.1, 300.1; found277.9, 299.7.

Step 2. methyl1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate

Sodium hydride in mineral oil (45 mg, 1.9 mmol) was added to a solutionof methyl 1-hydroxycyclopropanecarboxylate (40 mg, 0.3 mmol) intetrahydrofuran (5 mL). After 10 min 15-Crown-5 (10 μL, 0.05 mmol) and1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene (100 mg, 0.3 mmol)were added. This mixture was stirred overnight at room temperature andwas then quenched with MeOH (1 mL). The resulting mixture waspartitioned between ethyl acetate and water, and the combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated to yield crude material. The product was purified by FCC onsilica gel eluting a hexane: ethyl acetate gradient to afford methyl1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate asa glass (45 mg, 30%). LCMS calculated for C₁₂H₁₃BrNO₇S (M+H)⁺:m/z=394.1, 396.1; found 393.7, 395.8.

Step 3.8-bromo-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Iron filings (20 mg, 0.4 mmol) were added to a solution of methyl1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate (40mg, 0.1 mmol) in acetic acid (3 mL). The reaction was heated at 60° C.for 3 h, diluted with ethyl acetate, filtered, and concentrated. Theresidue was then dissolved in ethyl acetate and washed with saturatedNaHCO₃. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated to afford8-bromo-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-oneas crude material. LCMS calculated for C₁₁H₁₁BrNO₄S (M+H)⁺: m/z=332.0,334.0; found 331.8, 333.8.

Step 4.8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Using methods similar to conditions in Example 44, but using8-bromo-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-onefrom Step 3, the crude product was prepared. The product was purified byprep HPLC on a C-18 column eluting a water: acetonitrile gradientbuffered at pH 10 to afford the title compound as an off white amorphoussolid (10 mg, 30%). LCMS calculated for C₁₉H₁₈N₃O₅S (M+H)⁺: m/z=400.1;found=400.0.

Example 58.3,3-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-7-(methylsulfonyl)-3,4-dihydroquinoxalin-2(1H)-one

Step 1. methyl2-{[2-bromo-4-(methylsulfonyl)-6-narophenyl]amino}-2-methylpropanoate

A mixture of 1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene (70 mg,0.2 mmol) from Example 57, methyl 2-amino-2-methylpropanoatehydrochloride (50 mg, 0.3 mmol) (Sigma Aldrich cat #A8754), and sodiumbicarbonate (40 mg, 0.5 mmol) in N-methylpyrrolidinone (4 mL) was heatedovernight at 100° C. The mixture was then cooled to room temperature andpartitioned between ethyl acetate and water. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated toyield crude material. The product was purified by FCC on silica geleluting a hexane: ethyl acetate gradient to afford methyl2-{[2-bromo-4-(methylsulfonyl)-6-nitrophenyl]amino}-2-methylpropanoateas a glass (60 mg, 60%). LCMS calculated for C₁₂H₁₆BrN₂O₆S (M+H)⁺:m/z=395.1, 397.1; found=395.0, 397.0.

Step 2.3,3-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-7-(methylsulfonyl)-3,4-dihydroquinoxahn-2(1H)-one

Using methods similar to conditions in Example 57, but using methyl2-{[2-bromo-4-(methylsulfonyl)-6-nitrophenyl]amino}-2-methylpropanoatefrom Step 1, the crude product was prepared. The product was purified byprep HPLC on a C-18 column eluting a water:acetonitrile gradientbuffered at pH 10 to afford the title compound as an off white amorphoussolid (12 mg, 30%). LCMS calculated for C₁₉H₂₁N₄O₄S (M+H)⁺: m/z=401.1;found=401.1. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H), 10.58 (s, 1H),7.31-7.24 (m, 3H), 7.21 (s, 1H), 6.02 (s, 1H), 5.68 (s, 1H), 3.55 (s,3H), 3.11 (s, 3H), 1.24 (s, 6H).

Examples 59-62

The compounds of Examples 59-62 and the experimental procedures used toprepare them are set out in Table 9 below.

TABLE 9

Ex. Synthetic No. Name R¹ R² Procedure 598′-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-6′-(methylsulfonyl)-1′,4′-dihydro- 3′H-spiro[cyclopentane-1,2′-quinoxalin]-3′-one

R¹ and R² taken together Ex. No. 58 60 (3S)-3-isopropyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-7-(methylsulfonyl)-3,4-dihydroquinoxalin-2(1H)-one

H Ex. No. 58 61 (3R)-3-isopropyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-7-(methylsulfonyl)-3,4-dihydroquinoxalin-2(1H)-one

H Ex. No. 58 62 8′-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6′- (methylsulfonyl)-1,4′-dihydro-3H-spiro[cyclobutane-1,2′-quinoxalin]- 3′-one

R¹ and R² taken together Ex. No. 58

Example 63.4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Step 1. 1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene

Nitric acid (0.42 mL, 10 mmol) was added drop wise to a solution of1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (2 g, 9 mmol) in sulfuricacid (10 mL) and bromine (1 g, 9 mmol) and the reaction was heated to80° C. for 5 hrs. The reaction was allowed to cool to rt and was pouredinto ice. The aqueous layer was extracted with methylene chloride. Thecombined organic layer was washed with saturated Na₂S₂O₃, brine, driedover MgSO₄, filtered and concentrated to give the crude material. Theproduct was purified by FCC on silica gel eluting with a hexane: ethylacetate gradient to obtain1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene as a white solid(0.80 g, 30%).

Step 2. Methyl1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate

Sodium hydride in mineral oil (110 mg, 4.7 mmol) was added to a solutionof methyl 1-hydroxycyclopropanecarboxylate (100 mg, 0.8 mmol) inN,N-dimethylformamide (20 mL) at 0° C. After 5 min,1-bromo-2-fluoro-5-(methylsulfonyl)-3-nitrobenzene (250 mg, 0.84 mmol)was added and the reaction was stirred at 0° C. for 1 h. The reactionwas quenched with MeOH (3 mL) and partitioned between water and ethylacetate. The combined organic layer was washed with brine, dried overMgSO₄, filtered and concentrated to give crude material. The product waspurified by FCC on silica gel eluting with hexane:ethyl acetate gradientto give methyl1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate asa yellow oil (0.10 g, 67%). LCMS calculated for C₁₂H₁₃BrNO₇S (M+H)⁺:m/z=394.0 396.0; found: 394.0, 395.9.

Step 3.8-bromo-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Iron powder (500 mg, 8 mmol) was added to a solution of methyl1-[2-bromo-4-(methylsulfonyl)-6-nitrophenoxy]cyclopropanecarboxylate(700 mg, 2 mmol) in acetic acid (40 mL) which was degassed withnitrogen. The reaction was heated at 60° C. for 3 hrs. The reaction wasallowed to cool to rt, diluted with ethyl acetate, filtered andconcentrated. The residue was portioned between ethyl acetate andsaturated NaHCO₃. The combined organic layer was washed with brine,dried over MgSO₄, filtered and concentrated to give crude material as asolid (0.50 g, 90%). LCMS calculated for C₁₁H₁₁BrNO₄S (M+H)⁺: m/z=331.9,333.9; found: 331.9, 333.8.

Step 4.8-Bromo-4-methyl-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

Sodium hydride in mineral oil (30 mg, 1.3 mmol) was added to a mixtureof8-bromo-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one(280 mg, 0.84 mmol) in N,N-dimethylformamide (50 mL) at 0° C. Thereaction was stirred for 20 min and methyl iodide (63 μL, 1.0 mmol) wasadded and stirred for 30 min at rt. The reaction was quenched withmethanol and partitioned between ethyl acetate and water. The combinedorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated to give crude material. The product was purified by FCC onsilica gel eluting with hexane:ethyl acetate gradient to give8-bromo-4-methyl-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-oneas a semisolid (0.286 g, 96%). LCMS calculated for C₁₂H₁₃BrNO₄S (M+H)⁺:m/z=346.1 and 348.1; found: 346.1, 348.1.

Step 5.4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

8-Bromo-4-methyl-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one(260 mg, 0.75 mmol) and6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(390 mg, 0.90 mmol) were dissolved in 1,4-dioxane (40 mL) with cesiumfluoride (300 mg, 2 mmol) in water (10 mL) and the reaction was degassedwith nitrogen. The catalyst4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(200 mg, 0.2 mmol) was added, degassed with nitrogen and the reactionwas heated to 100° C. for 2 hrs. The reaction was allowed to cool to rtand partitioned between ethyl acetate and water. The combined organiclayer was washed with brine and dried over MgSO₄, filtered andconcentrated to give crude material. The product was purified by FCC onsilica gel eluting hexane:ethyl acetate gradient to give4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-oneas a solid residue (0.27 g, 63%). LCMS calculated for C₂₇H₂₆N₃O₇S₂(M+H)⁺: m/z=568.1; found: 568.1.

Step 6.4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

1.0 M Sodium hydroxide in water (2 mL, 2 mmol) was added to a solutionof4-methyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-onein ethanol (6 mL). The reaction was stirred at 80° C. for 2 h, thenallowed to cool to rt. The product was purified without workup by prepHPLC on a C-19 column eluting with a water:acetonitrile gradientbuffered pH 10 to give the title compound as a white amorphous solid(0.12 g, 39%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H), 7.62 (d, J=2.1Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.25 (s, 1H),6.14 (d, J=2.8 Hz, 1H), 3.54 (s, 3H), 3.42 (s, 3H), 3.29 (s, 3H),1.32-1.25 (m, 2H), 1.16-1.10 (m, 2H). LCMS calculated for C₂₀H₂₀N₃O₅S(M+H)⁺: m/z=414.1; found: 414.1.

Example 64.8′-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6′-(methylsulfonyl)-1′,4′-dihydro-3′H-spiro[cyclohexane-1,2′-quinoxalin]-3′-one

The compound of Example 64 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compound ofExample 58 to afford the title compound as a white amorphous solid (5mg,10%). LCMS found (M+H)⁺=441.2.

Examples 65-66

The compounds of Examples 65-66 and the experimental procedures used toprepare them are set out in Table 10 below.

TABLE 10

Ex. Synthetic No. Name R¹ R² R³ Procedure 658-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrazolo[3,4-c]pyridin-4-yl)-6-(methylsulfonyl)spiro [1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

R¹ and R² taken together H Ex. Nos. 57, 26 664-methyl-8-(6-methyl-7-oxo- 6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-6-(methylsulfonyl) spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one

R¹ and R² taken together CH₃— Ex. Nos. 57, 26, 8

Example 67.2-isopropyl-N,N-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide

Step 1. 4-hydroxy-N,N-dimethyl-3-nitrobenzenesulfonamide

2.0 M Dimethylamine in THF (0.2 mL, 0.4 mmol) was added to a mixture of4-hydroxy-3-nitrobenzenesulfonyl chloride (100 mg, 0.4 mmol) (Matrix cat#084425) and 4-N,N-dimethylaminopyridine (50 mg, 0.4 mmol) intetrahydrofuran (5 mL) at room temperature. The reaction mixture wasstirred overnight then partitioned between ethyl acetate and 1 N HCl.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to afford crude4-hydroxy-N,N-dimethyl-3-nitrobenzenesulfonamide as a solid (90 mg,90%). LCMS calculated for C₈H₁₁N₂O₅S (M+H)⁺: m/z=247.1; found=247.0.

Step 2. 3-bromo-4-hydroxy-N,N-dimethyl-5-nitrobenzenesulfonamide

Bromine (10 μL, 0.2 mmol) was added to a solution of4-hydroxy-N,N-dimethyl-3-nitrobenzenesulfonamide (50 mg, 0.2 mmol) inacetic acid (2 mL) and ferric chloride (7 mg, 0.04 mmol) in water (0.5mL) at room temperature. The reaction was stirred overnight at roomtemperature then partitioned between saturated NaHCO₃ and ethyl acetate.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to afford crude3-bromo-4-hydroxy-N,N-dimethyl-5-nitrobenzenesulfonamide (60 mg, 80%) asa glass. LCMS calculated for C₈H₁₀BrN₂O₅S (M+H)⁺: m/z=325.1, 327.1;found=324.9, 326.9.

Step 3. 3-amino-5-bromo-4-hydroxy-N,N-dimethylbenzenesulfonamide

Raney Nickel (25 mg) was added to a solution of3-bromo-4-hydroxy-N,N-dimethyl-5-nitrobenzenesulfonamide (50 mg, 0.2mmol) in ethanol (5 mL) in a Parr shaker bottle. The mixture wasdegassed with nitrogen and charged to 30 psi hydrogen. The mixture wasshaken for 2 h, filtered, and concentrated to afford crude3-amino-5-bromo-4-hydroxy-N,N-dimethylbenzenesulfonamide as a yellow oil(40 mg, 90%). LCMS calculated for C₈H₁₂BrN₂O₃S (M+H)⁺: m/z=295.1, 297.1;found=295.0, 297.0.

Step 4.2-isopropyl-N,N-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide

Using methods similar to conditions in Example 9, but using3-amino-5-bromo-4-hydroxy-N,N-dimethylbenzenesulfonamide from Step 3,the crude product was prepared. The product was purified by prep HPLC ona C-18 column eluting a water:acetonitrile gradient buffered at pH 10 toafford the title compound as a white amorphous solid (4 mg, 40%). LCMScalculated for C₂₁H₂₅N₄O₅S (M+H)⁺: m/z=445.1; found=445.2. ¹H NMR (300MHz, DMSO-d₆) δ 12.1 (s, 1H), 7.35 (s, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.22(m, 1H), 7.11 (m, 1H), 6.16 (d, J=2.7 Hz, 1H), 4.4 (d, 1H), 3.54 (s,3H), 2.62 (s, 3H), 2.48 (s, 3H), 2.3-2.2 (m, 1H), 0.80 (dd, 6H).

Example 75.2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

Step 1. 4-(methylthio)phenol

4-Mercaptophenol (0.5 g, 4 mmol) (Aldrich cat #559938-5) was dissolvedin acetone (10.0 mL), then potassium carbonate (0.684 g, 4.95 mmol) andiodomethane (0.396 mL, 4.95 mmol) were added. The reaction mixture wasstirred at room temperature for 2 h, diluted with ethyl acetate, andfiltered. The organic layer was concentrated in vacuo to yield a yellowoil. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to afford 4-(methylthio)phenol as a clear oilwhich crystallized upon sitting (0.55 g, 80%).

Step 2. 4-(methylsulfonyl)phenol

Oxone (0.99 g, 6.5 mmol) (Aldrich cat #22803-6) was added in portions toa solution of 4-(methylthio)phenol (0.50 g, 3.2 mmol) in ethanol (10.0mL) and water (10.0 mL) at room temperature. The reaction mixture wasstirred for 18 h then partitioned between ethyl acetate and water. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, and concentrated in vacuo to afford 4-(methylsulfonyl)phenol asa semisolid (0.60 g, 96%). LCMS calculated for C₇H₉O₃S (M+H)⁺:m/z=173.0; found: 173.0.

Step 3. 4-(methylsulfonyl)-2-nitrophenol

Nitric acid (0.1 mL, 3 mmol) was added to a mixture of4-(methylsulfonyl)phenol (0.5 g, 3 mmol) in acetic acid (9 mL) at roomtemperature. The mixture was heated to 80° C. for 3 h then cooled toroom temperature and partitioned between ethyl acetate and water. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to yield crude product. The product wascrystallized from ethyl ether to afford 4-(methylsulfonyl)-2-nitrophenolas a pale yellow solid (0.59 g, 100%). LCMS calculated for C₇H₈NO₅S(M+H)⁺: m/z=218.1; found: 218.0.

Step 4. 2-bromo-4-(methylsulfonyl)-6-nitrophenol

Bromine (0.41 g, 2.6 mmol) in acetic acid (5 mL) was added to a solutionof 4-(methylsulfonyl)-2-nitrophenol (0.63 g, 2 mmol) in acetic acid (20mL) and ferric chloride (0.08 g, 0.5 mmol) in water (0.3 mL) at roomtemperature and the resulting mixture was stirred for 4 h. This mixturewas then diluted with water (70 mL), forming a slurry. The solids werecollected, washed with water, and dried to afford2-bromo-4-(methylsulfonyl)-6-nitrophenol as an off white powder (0.75gm, 80%). LCMS calculated for C₇H₇BrNO₅S (M+H)⁺: m/z=295.9, 297.9;found: 296.0, 298.0.

Step 5. 2-amino-6-bromo-4-(methylsulfonyl)phenol

2-Bromo-4-(methylsulfonyl)-6-nitrophenol (0.20 g, 0.64 mmol) wasdissolved in ethanol (7.0 mL, 120 mmol), degassed with nitrogen, andthen Raney Nickel (75 mg) was added. The reaction mixture was stirredunder a hydrogen atmosphere for 2 h. The mixture was decanted from thesolids and concentrated in vacuo to afford2-amino-6-bromo-4-(methylsulfonyl)phenol as a glass (0.19 g, 95%). LCMScalculated for C₇H₉BrNO₃S (M+H)⁺: m/z=266.1, 268.1; found: 266.0, 268.0.

Step 6.8-bromo-2,2-dimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

2-Bromo-2-methyl-propanoyl bromide (0.41 mL, 3.4 mmol) (Aldrich cat#252271) was added slowly to a solution of2-amino-6-bromo-4-(methylsulfonyl)phenol (0.75 g, 2.8 mmol) inacetonitrile (49.7 mL) and potassium carbonate (1.6 g, 11 mmol) in water(16 mL) at rt. The reaction was stirred for 1 h and was heated to 80° C.in an oil bath to cyclize. The reaction was heated for 18 h and wasallowed to cool to rt. The reaction was partitioned between ethylacetate and water. The combined organic layer was washed with brine,dried over magnesium sulfate and concentrated to give a dark oil. Theproduct was purified by FCC on silica gel eluting hexane:ethyl acetategradient to give8-bromo-2,2-dimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one as asolid (0.84 g, 89%). LCMS calculated for C₁₁H₁₃BrNO₄S (M+H)⁺: m/z=334.1,336.1; found: 334.0, 336.0.

Step 7.8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

Sodium hydride (0.12 g, 2.9 mmol) was added to a solution of8-bromo-2,2-dimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one(0.82 g, 2.4 mmol) in N,N-dimethylformamide (23.4 mL) under nitrogen atrt. The reaction was stirred for 30 minutes and methyl iodide (0.30 mL,4.9 mmol) was added. After stirring for 1 h the reaction was partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over magnesium sulfate and concentrated to give8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-oneas a solid residue (0.83 g, 97%). LCMS calculated for C₁₂H₁₅BrNO₄S(M+H)⁺: m/z=348.1, 350.1; found: 348.0, 350.0.

Step 8.2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

Using methods similar to conditions in Example 9, but using8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-onefrom Step 7, the crude product was prepared. The product was purified byprep HPLC on a C-18 column eluting with a water:acetonitrile gradientbuffered at pH 10 to afford the title compound as an off white amorphoussolid (25 mg, 30%). LCMS calculated for C₂₀H₂₂N₃O₅S (M+H)⁺: m/z=416.1;found 416.1. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.63 (d, J=1.7Hz, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.30 (d, J=2.7 Hz, 2H), 6.15 (d, J=2.1Hz, 1H), 3.56 (s, 3H), 3.40 (s, 3H), 3.28 (s, 3H), 1.38 (s, 6H).

Example 76.6-(ethylsulfonyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

Step 1.8-bromo-6-(ethylsulfonyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one

Potassium carbonate (200 mg, 1 mmol) was added to a solution of2-amino-6-bromo-4-(ethylsulfonyl)phenol (180 mg, 0.64 mmol) from Example51, Step 5, in acetonitrile (2 mL) and 2-bromo-2-methyl-propanoic acidethyl ester (520 mg, 2.7 mmol). The reaction was heated to 80° C. for 3hrs. The reaction was filtered, concentrated and purified by FCC onsilica gel eluting with a hexane:ethyl acetate gradient to afford8-bromo-6-(ethylsulfonyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one aswhite solid (124 mg, 54%). LCMS calculated for C₁₂H₁₅BrNO₄S (M+H)⁺:m/z=348.1, 350.1; found:347.8, 349.9.

Step 2.8-bromo-6-(ethylsulfonyl)-2,2,4-trimethyl-2H-1,4-benzoxazin-3(4H)-one

Sodium hydride in mineral oil (19 mg, 0.78 mmol) was added to a mixtureof 8-bromo-6-(ethylsulfonyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one(180 mg, 0.52 mmol) in N,N-dimethylformamide (30 mL) at 0° C. Thereaction was stirred for 20 min and methyl iodide (39 μL, 0.62 mmol) wasadded and stirred for 30 min at rt. The reaction was quenched with MeOHand partitioned between water and ethyl acetate. The combined organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedto give crude8-bromo-6-(ethylsulfonyl)-2,2,4-trimethyl-2H-1,4-benzoxazin-3(4H)-one asa foam (280 mg, 96%). LCMS calculated for C₁₃H₁₇BrNO₄S (M+H)⁺:m/z=362.0, 364.0; found:362.0, 364.0.

Step 3.6-(ethylsulfonyl)-2,2,4-trimethyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-one

8-Bromo-6-(ethylsulfonyl)-2,2,4-trimethyl-2H-1,4-benzoxazin-3(4H)-one(200 mg, 0.6 mmol) and6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one(280 mg, 0.66 mmol) were dissolved in 1,4-dioxane (30 mL) with cesiumfluoride (200 mg, 2 mmol) in water (10 mL) and was degassed withnitrogen. The catalyst4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(100 mg, 0.2 mmol) was added, degassed with N₂ and the reaction washeated to 100° C. for 2 h. The reaction was allowed to cool to rt,diluted with ethyl acetate and washed with water, brine and dried overMgSO₄, then filtered and concentrated to give crude material. Theproduct was purified by FCC on silica gel eluting with hexane:ethylacetate gradient to obtain6-(ethylsulfonyl)-2,2,4-trimethyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-oneas a glass (200 mg, 60%). LCMS calculated for C₂₈H₃₀N₃O₇S₂ (M+H)⁺:m/z=584.1; found:584.2.

Step 4.6-(ethylsulfonyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one

1.0 M Sodium hydroxide in water (1 mL, 1 mmol) was added to a solutionobtain6-(ethylsulfonyl)-2,2,4-trimethyl-8-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-2H-1,4-benzoxazin-3(4H)-onein ethanol (4 mL). The reaction was stirred at 80° C. for 2 h, allowedto cool to rt and purified by prep HPLC without workup on a C-18 columneluting with a water: acetonitrile gradient buffered pH 10 to give thetitle compound as a white amorphous solid (110 mg, 50%). ¹H NMR (300MHz, DMSO-d₆) δ 12.12 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.52 (d, J=2.0Hz, 1H), 7.30 (d, J=2.6 Hz, 2H), 6.13 (d, J=2.1 Hz, 1H), 3.56 (s, 3H),3.39 (s, 3H), 3.34 (q, J=7.4 Hz, 2H), 1.38 (s, 6H), 1.14 (t, J=7.3 Hz,3H). LCMS calculated for C₂₁H₂₄N₃O₅S (M+H)⁺: m/z=430.1; found:430.1.

Examples 68-83

The compounds of Examples 68-83 and the experimental procedures used toprepare them are set out in Table 11 below.

TABLE 11

Ex. Synthetic No. Name R¹ R² R³ R⁵ Procedure 682-isopropyl-N-methyl-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide i-Prop H H

Ex. No. 67 69 N,N,2,2,4-pentamethyl-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide CH₃— CH₃— CH₃—

Ex. Nos. 67, 8 70 N,N,2,2-tetramethyl-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide CH₃— CH₃— CH₃—

Ex. No. 67 71 2-isopropyl-N,N,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro- 2H-1,4-benzoxazine-6- sulfonamide i-Prop H CH₃—

Ex. Nos. 67, 8 72 2,2-dimethyl-8-(6-methyl-7- oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6- (piperidin-1-ylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one CH₃— CH₃— H

Ex. No. 67 73 2,2,4-trimethyl-8-(6-methyl-7- oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6- (piperidin-1-ylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one CH₃— CH₃— CH₃—

Ex. Nos. 67, 8 74 N-isopropyl-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4- benzoxazine-6-sulfonamide CH₃— CH₃— H

Ex. No. 67 75 2,2,4-trimethyl-8-(6-methyl-7- oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6- (methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one CH₃— CH₃— CH₃—

Ex. No. 75 76 6-(ethylsulfonyl)-2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4- benzoxazin-3(4H)-oneCH₃— CH₃— CH₃—

Ex. No. 76 77 6-(isopropylsulfonyl)-2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4- benzoxazin-3(4H)-oneCH₃— CH₃— CH₃—

Ex. Nos. 51, 8 78 6-(ethylsulfonyl)-2,2- dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4- benzoxazin-3(4H)-oneCH₃— CH₃— H

Ex. No. 51 79 6-(isopropylsulfonyl)-2,2- dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4- benzoxazin-3(4H)-oneCH₃— CH₃— H

Ex. No. 51 80 6-acetyl-2,2-dimethyl-8-(6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)-2H-1,4-benzoxazin-3(4H)- one CH₃— CH₃— H

Ex. No. 9 81 6-(1-hydroxyethyl)-2,2- dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4- benzoxazin-3(4H)-oneCH₃— CH₃— H

Ex. Nos. 80, 50 82 6-acetyl-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)- one CH₃— CH₃— CH₃—

Ex. Nos. 9, 8 83 6-(1-hydroxyethyl)-2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] pyridin-4-yl)-2H-1,4- benzoxazin-3(4H)-oneCH₃— CH₃— CH₃—

Ex. Nos. 82, 50

Example 83A.6-(1-hydroxyethyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 1) Example 83B.6-(1-hydroxyethyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one(Enantiomer 2)

The enantiomers of the compound of Example 83 were separated by prepchiral column chromatography using the following conditions: Column:phenomenex Lux Cellulose C-2, 5 μm, 21, 2×250 mm; Mobile phase: 60%EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 9.0mg in 900 μL, run time: 11 min; peak retention times: 6.4 and 8.5 min.

Example 83A, Peak 1 (6.4 min) LCMS calculated for C₂₁H₂₄N₃O₄ (M+H)⁺:m/z=382.1; found: 382.1. ¹H NMR (300 MHz, DMSO-d₆) δ 11.99 (s, 1H), 7.22(t, J=2.7 Hz, 1H), 7.12 (s, 1H), 7.04 (s, 2H), 6.08 (t, J=2.3 Hz, 1H),5.14 (d, J=4.3 Hz, 1H), 4.77-4.60 (m, 1H), 3.50 (s, 3H), 3.27 (s, 3H),1.30 (d, J=6.4 Hz, 3H), 1.27 (s, 6H).

Example 83B, Peak 2 (8.5 min) LCMS calculated for C₂₁H₂₄N₃O₄ (M+H)⁺:m/z=382.1; found: 382.1. ¹H NMR (300 MHz, DMSO-d₆) δ 11.99 (s, 1H), 7.22(t, J=2.7 Hz, 1H), 7.12 (s, 1H), 7.04 (s, 2H), 6.08 (t, J=2.3 Hz, 1H),5.14 (d, J=4.3 Hz, 1H), 4.77-4.60 (m, 1H), 3.50 (s, 3H), 3.27 (s, 3H),1.30 (d, J=6.4 Hz, 3H), 1.27 (s, 6H).

Example 84.2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

The compound of Example 84 was synthesized according to an experimentalprocedure analogous to that used for the synthesis of the compounds ofExamples 44 and 26 to afford the title compound as a white amorphoussolid (12 mg, 20%). LCMS found (M+H)⁺=417.1. ¹H NMR (300 MHz, DMSO-d₆) δ11.06 (s, 1H), 7.86 (bs, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.44 (bs, 1H),7.41 (d, J=2.0 Hz, 1H), 4.71 (d, J=3.7 Hz, 1H), 3.58 (s, 3H), 3.22 (s,3H), 2.33-2.17 (m, 1H), 0.78 (d, J=6.7 Hz, 3H), 0.72 (d, J=6.9 Hz, 3H).

Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of Examples 2-4, 13-16, 23-24, 33-34, 40-41,45-49, 52-56, 59-62, 65-66, and 68-83 are provided below in Table 12.

TABLE 12 Ex. MS No. [M + H]⁺ ¹H NMR Spectra 2 338.1 ¹H NMR (300 MHz,DMSO-d₆) δ 12.01 (s, 1H), 10.69 (s, 1H), 7.26 (s, 2H), 7.08-6.92 (m,2H), 6.91-6.81 (m, 1H), 6.17 (bs, 1H), 4.39 (d, J = 4.1 Hz, 1H), 3.53(s, 3H), 2.21 (dd, J = 11.3, 6.4 Hz, 1H), 0.81 (dd, J = 7.7 Hz, 6H). 3310.0 ¹H NMR (500 MHz, DMSO-d₆) δ 11.98 (s, 1H), 10.67 (s, 1H), 7.26 (s,1H), 7.21 (s, 1H), 7.06-6.95 (m, 2H), 6.94-6.86 (m, 1H), 6.17 (s, 1H),4.68 (q, J = 6.6 Hz, 1H), 3.54 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H). 4324.1 ¹H NMR (500 MHz, DMSO-d₆) δ 11.98 (s, 1H), 10.68 (s, 1H), 7.26 (t,J = 2.6 Hz, 1H), 7.23 (s, 1H), 7.06-6.96 (m, 2H), 6.90 (q, J = 4.7, 4.1Hz, 1H), 6.20-6.11 (m, 1H), 4.50 (dd, J = 8.0, 4.2 Hz, 1H), 3.54 (s,3H), 1.88-1.75 (m, 1H), 1.72-1.60 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H). 13425.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.62 (s, 1H), 7.37-7.13(m, 3H), 6.65 (d, J = 2.7 Hz, 1H), 6.45 (d, J = 2.7 Hz, 1H), 6.26-6.12(m, 1H), 4.61-4.37 (m, 2H), 4.35 (d, J = 5.0 Hz, 1H), 3.73 (s, 3H), 3.54(s, 3H), 2.16 (dd, J = 12.0, 6.7 Hz, 1H), 0.81 (d, J = 6.9 Hz, 3H), 0.75(d, J = 6.7 Hz, 3H). 14 508.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (s, 1H),7.28 (dd, J = 6.1, 3.3 Hz, 2H), 6.66 (d, J = 2.7 Hz, 1H), 6.52 (d, J =2.7 Hz, 1H), 6.20 (s, 1H), 5.08- 4.90 (m, 1H), 4.86-4.67 (m, 1H),4.46-4.35 (m, 1H), 4.32 (d, J = 5.5 Hz, 1H), 4.27-4.12 (m, 1H), 3.73 (s,3H), 3.54 (s, 3H), 3.51-3.38 (m, 4H), 3.21-3.06 (m, 1H), 3.06-2.91 (m,1H), 2.85 (s, 3H), 2.20-2.04 (m, 1H), 0.81 (d, J = 6.9 Hz, 3H), 0.74 (d,J = 6.6 Hz, 3H). 15 459.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (s, 1H),8.71 (d, J = 6.2 Hz, 2H), 7.60 (d, J = 5.9 Hz, 2H), 7.29 (d, J = 4.3 Hz,2H), 6.67 (d, J = 2.7 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.23 (s, 1H),5.49-5.22 (m, 2H), 4.58 (d, J = 4.6 Hz, 1H), 3.66 (s, 3H), 3.55 (s, 3H),2.35-2.15 (m, 1H), 0.82 (dd, J = 6.9 Hz, 6H). 16 410.2 ¹H NMR (300 MHz,DMSO-d₆) δ 12.02 (s, 1H), 7.32-7.21 (m, 2H), 6.76 (d, J = 2.7 Hz, 1H),6.66 (d, J = 2.7 Hz, 1H), 6.19 (d, J = 2.2 Hz, 1H), 4.64- 4.49 (m, 1H),4.15 (d, J = 5.0 Hz, 1H), 3.76 (s, 3H), 3.53 (s, 3H), 2.15- 2.02 (m,1H), 1.47 (d, J = 6.8 Hz, 6H), 0.78 (d, J = 6.9 Hz, 3H), 0.71 (d, J =6.7 Hz, 3H). 23 366.1 ¹H NMR (300 MHz, DMSO-d₆) δ 11.69 (s, 1H), 10.28(s, 1H), 6.93 (d, J = 4.3 Hz, 2H), 6.21 (d, J = 2.8 Hz, 1H), 6.12 (d, J= 2.9 Hz, 1H), 5.86 (s, 1H), 3.64 (d, J = 8.2 Hz, 1H), 3.36 (s, 3H),3.20 (s, 3H), 0.88-0.73 (m, 1H), 0.28-0.14 (m, 1H), 0.12-0.03 (m, 1H),0.03-−0.06 (m, 2H). 24 402.1 ¹H NMR (300 MHz, DMSO-d₆) δ 11.93 (s, 1H),10.90 (s, 1H), 7.28-7.17 (m, 4H), 7.13 (t, J = 2.7 Hz, 1H), 7.02 (s,1H), 6.49 (d, J = 2.9 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 5.99 (s, 1H),5.61 (s, 1H), 3.65 (s, 3H), 3.42 (s, 3H). 33 451.2 ¹H NMR (300 MHz,DMSO-d₆) δ 12.04 (s, 1H), 10.83 (s, 1H), 7.34-7.23 (m, 2H), 7.04 (d, J =1.9 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 6.23-6.12 (m, 1H), 4.49 (d, J =4.0 Hz, 1H), 3.63-3.55 (m, 4H), 3.54 (s, 3H), 3.54-3.45 (m, 4H)2.29-2.17 (m, 1H), 0.81 (dd, 6H). 34 409.2 ¹H NMR (300 MHz, DMSO-d₆) δ12.04 (s, 1H), 10.81 (s, 1H), 7.30 (s, 1H), 7.27 (t, J = 2.7 Hz, 1H),7.03 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.17 (t, J = 2.2 Hz,1H), 4.49 (d, J = 3.9 Hz, 1H), 3.54 (s, 3H), 2.96 (s, 6H), 2.29-2.17 (m,1H), 0.87-0.75 (m, 6H). 40 409.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s,1H), 10.68 (s, 1H), 8.33 (t, J = 5.8 Hz, 1H), 7.27 (t, J = 2.5 Hz, 1H),7.25 (s, 1H), 6.93 (s, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.20 (s, 1H), 4.35(d, J = 4.3 Hz, 1H), 4.16 (d, J = 5.9 Hz, 2H), 3.53 (s, 3H), 2.19 (dd, J= 11.1, 6.8 Hz, 1H), 1.83 (s, 3H), 0.81 (dd, J = 13.7, 6.8 Hz, 6H). 41381.1 ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.84 (s, 1H), 7.87 (s,1H), 7.55 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.29 (s, 1H),7.26-7.21 (m, 2H), 6.18 (t, J = 2.2 Hz, 1H), 4.48 (d, J = 4.0 Hz, 1H),3.55 (s, 3H), 2.28-2.13 (m, 1H), 0.79 (d, J = 6.8 Hz, 6H). 45 402.1 ¹HNMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 10.97 (bs, 1H), 7.55 (d, J = 2.2Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.30 (s, 2H), 6.17 (d, J = 2.4 Hz,1H), 3.56 (s, 3H), 3.21 (s, 3H), 1.38 (s, 6H). 46 450.1 ¹H NMR (300 MHz,DMSO-d₆) δ 11.99 (s, 1H), 11.29 (bs, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.41(d, J = 2.1 Hz, 1H), 7.32-7.21 (m, 5H), 7.20-7.10 (m, 2H), 6.00 (s, 1H),5.87 (s, 1H), 3.44 (s, 3H), 3.17 (s, 3H). 47 430.1 ¹H NMR (300 MHz,DMSO-d₆) δ 12.06 (s, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 2.1 Hz,1H), 7.34 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H),4.59 (d, J = 4.2 Hz, 1H), 3.51 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H),2.25-2.13 (m, 1H), 0.73 (dd, J = 6.7, 4.8 Hz, 6H). 48 418.1 ¹H NMR (300MHz, DMSO-d₆) δ 12.11 (s, 1H), 11.03 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H),7.44-7.35 (m, 2H), 7.30 (t, J = 2.7 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H),4.82 (dd, J = 9.3, 3.4 Hz, 1H), 4.51 (t, J = 5.3 Hz, 1H), 3.56 (s, 3H),3.36-3.28 (m, 2H), 3.21 (s, 3H), 2.12-1.95 (m, 1H), 1.87-1.70 (m, 1H).49 380.1 ¹H NMR (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 10.84 (s, 1H), 7.61(d, J = 2.1 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.28 (s, 1H), 7.23 (t, J= 2.6 Hz, 1H), 6.15 (s, 0H), 4.51 (d, J = 4.0 Hz, 1H), 3.50 (s, 3H),2.47 (s, 3H), 2.24-2.09 (m, 1H), 0.75 (dd, J = 6.8, 3.1 Hz, 6H). 52444.1 ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (s, 1H), 10.92 (s, 1H), 7.36 (d,J = 2.2 Hz, 1H), 7.33 (s, 1H), 7.24 (dd, J = 5.0, 2.5 Hz, 2H), 6.12 (d,J = 2.8 Hz, 1H), 4.54 (d, J = 3.8 Hz, 1H), 3.50 (s, 3H), 3.39-3.29 (m,1H), 2.27-2.14 (m, 1H), 1.12 (d, J = 6.7 Hz, 6H), 0.76 (dd, J = 6.8, 4.4Hz, 6H). 53 470.2 54 444.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H),7.58 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.33 (s, 1H), 7.24(d, J = 2.7 Hz, 1H), 6.14 (d, J = 2.7 Hz, 1H), 4.56 (d, J = 4.5 Hz, 1H),4.08-3.90 (m, 2H), 3.50 (s, 3H), 3.24 (s, 3H), 2.24-2.08 (m, 1H), 1.15(t, J = 6.9 Hz, 3H), 0.72 (dd, J = 6.8 Hz, 6H). 55 444.2 ¹H NMR (300MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.51 (d, J =1.9 Hz, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.17 (s, 1H), 4.65 (d, J = 4.1Hz, 1H), 3.55 (s, 3H), 3.38 (s, 3H), 3.36-3.31 (m, 1H), 2.34-2.17 (m,1H), 1.14 (t, J = 7.3 Hz, 3H), 0.79 (dd, J = 6.5 Hz, 6H). 56 458.2 ¹HNMR (300 MHz, DMSO-d₆) δ 12.07 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.41(d, J = 2.0 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J = 2.8 Hz, 1H), 6.10 (d, J= 2.7 Hz, 1H), 4.60 (d, J = 4.1 Hz, 1H), 3.50 (s, 3H), 3.49-3.43 (m,1H), 3.33 (s, 3H), 2.28-2.17 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H), 0.75(dd, J = 7.3 Hz, 6H). 59 427.1 ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (s,1H), 10.59 (s, 1H), 7.26-7.18 (m, 3H), 7.14 (s, 1H), 5.95 (s, 1H), 5.64(s, 1H), 3.48 (s, 3H), 3.06 (s, 3H), 2.02-1.88 (m, 2H), 1.65-1.44 (m,6H). 60 415.1 61 415.1 62 413.1 ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (s,1H), 10.59 (s, 1H), 7.29 (d, J = 2.7 Hz, 1H), 7.25 (s, 2H), 7.24 (s,1H), 6.30 (s, 1H), 6.02 (d, J = 2.7 Hz, 1H), 3.56 (s, 3H), 3.10 (s, 3H),2.43 (t, J = 9.4 Hz, 2H), 2.15 (q, J = 9.9 Hz, 2H), 1.81-1.69 (m, 1H),1.66-1.54 (m, 1H). 65 401.1 ¹H NMR (300 MHz, DMSO-d₆) δ 7.78 (s, 1H),7.49 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.30 (s, 1H), 5.69(s, 1H), 3.50 (s, 3H), 3.18(s, 3H), 1.26-1.18 (m, 2H), 1.06-0.97 (m,2H). 66 415.1 ¹H NMR (300 MHz, DMSO-d₆) δ 7.77 (s, 1H), 7.58 (s, 1H),7.57 (s, 1H), 7.30 (s, 1H), 3.51 (s, 3H), 3.36 (s, 3H), 3.25 (s, 3H),1.27-1.19 (m, 2H), 1.08-0.99 (m, 2H). 68 431.2 ¹H NMR (300 MHz, DMSO-d₆)δ 7.29 (s, 2H), 7.25 (d, J = 2.6 Hz, 1H), 7.15 (s, 1H), 6.18-6.08 (m,1H), 4.4-4.3(m, 1H), 3.50 (s, 3H), 2.37 (s, 3H), 2.22-2.09 (m, 1H), 0.76(dd, J = 9.1, 7.0 Hz, 6H). 69 445.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.13(s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.30 (t, J= 2.7 Hz, 1H), 7.29 (s, 1H), 6.11 (d, J = 2.2 Hz, 1H), 3.56 (s, 3H),3.38 (s, 3H), 2.66 (s, 6H), 1.39 (s, 6H). 70 431.1 ¹H NMR (300 MHz,DMSO-d₆) δ 12.11 (s, 1H), 10.93 (s, 1H), 7.33-7.29 (m, 2H), 7.29 (s,1H), 7.26 (s, 1H), 6.13 (s, 1H), 3.56 (s, 3H), 2.63 (s, 6H), 1.39 (s,6H). 71 459.1 72 471.1 ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.24(d, J = 2.7 Hz, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 6.07 (d,J = 2.7 Hz, 1H), 3.50 (s, 3H), 2.84 (bs, 4H), 1.54-1.30 (m, 6H), 1.27(s, 6H). 73 485.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 7.37 (d, J= 2.0 Hz, 1H), 7.26 (d, J = 2.8 Hz, 2H), 7.24 (s, 1H), 6.05 (d, J = 2.8Hz, 1H), 3.51 (s, 3H), 3.33 (s, 3H), 2.89 (bs, 4H), 1.55-1.36 (m, 6H),1.34 (s, 6H). 74 445.2 ¹H NMR (300 MHz, DMSO-d₆) δ 7.30 (s, 1H), 7.25(d, J = 2.8 Hz, 1H), 7.19 (s, 2H), 6.08 (d, J = 2.8 Hz, 1H), 3.50 (s,3H), 3.22-3.14 (m, 1H), 1.28 (s, 6H), 0.90 (d, J = 6.5 Hz, 6H). 75 416.1¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.63 (d, J = 1.7 Hz, 1H),7.59 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 2.7 Hz, 2H), 6.15 (d, J = 2.1 Hz,1H), 3.56 (s, 3H), 3.40 (s, 3H), 3.28 (s, 3H), 1.38 (s, 6H). 76 430.1 ¹HNMR (300 MHz, DMSO-d₆) δ 12.12 (s, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.52(d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.6 Hz, 2H), 6.13 (d, J = 2.1 Hz, 1H),3.56 (s, 3H), 3.39 (s, 3H), 3.34 (q, J = 7.4 Hz, 2H), 1.38 (s, 6H), 1.14(t, J = 7.3 Hz, 3H). 77 444.2 ¹H NMR (500 MHz, DMSO-d₆) δ 12.11 (s, 1H),7.55 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.33-7.26 (m, 2H),6.11 (d, J = 2.8 Hz, 1H), 3.57 (s, 3H), 3.55-3.49 (m, 1H), 3.39 (s, 3H),1.40 (s, 6H), 1.21 (d, J = 6.8 Hz, 6H). 78 416.1 ¹H NMR (300 MHz,DMSO-d₆) δ 12.13 (s, 1H), 11.01 (s, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.36(d, J = 2.2 Hz, 1H), 7.30 (s, 2H), 6.15 (s, 1H), 3.56 (s, 3H), 3.27 (q,J = 7.3 Hz, 1H), 1.39 (s, 6H), 1.13 (t, J = 7.3 Hz, 3H). 79 430.1 ¹H NMR(300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 8.53 (s, 1H), 7.38 (s, 1H),7.32-7.23 (m, 3H), 6.13 (d, J = 2.7 Hz, 1H), 3.56 (s, 3H), 3.41-3.34 (m,1H), 3.31 (s, 3H), 1.37 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). 80 366.2 81368.2 ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.63 (s, 1H), 7.27 (t,J = 2.7 Hz, 1H), 7.17 (s, 1H), 6.97 (d, J = 1.9 Hz, 1H), 6.89 (d, J =1.9 Hz, 1H), 6.20-6.09 (m, 1H), 5.14 (d, J = 4.0 Hz, 1H), 4.73-4.56 (m,1H), 3.54 (s, 3H), 1.38-1.25 (m, 9H). 82 380.2 ¹H NMR (300 MHz, DMSO-d₆)δ 12.08 (s, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H),7.28 (s, 1H), 7.26 (s, 1H), 6.14 (d, J = 2.6 Hz, 1H), 3.56 (s, 3H), 3.39(s, 3H), 2.59 (s, 3H), 1.36 (s, 6H). 83 382.2 ¹H NMR (300 MHz, DMSO-d₆)δ 11.99 (s, 1H), 7.22 (t, J = 2.7 Hz, 1H), 7.12 (s, 1H), 7.04 (s, 2H),6.08 (t, J = 2.3 Hz, 1H), 5.14 (d, J = 4.3 Hz, 1H), 4.77-4.60 (m, 1H),3.50 (s, 3H), 3.27 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.27 (s, 6H).

Example A1: BRD4 AlphaScreen™ Assay

BRD4 AlphaScreen™ Assay

BRD4-BD1 and BRD4-BD2 assays were conducted in white 384-wellpolystyrene plate in a final volume of 40 μL for BD1 and 60 μL for BD2.Inhibitors were first serially diluted in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 1.25% (BD1) and 0.83% (BD2). Theassays were carried out at room temperature in the assay buffer (50 mMTris-HCl, pH 7.5, 0.01% Tween-20, 0.01% BSA, 5 mM DTT), containing 50 nMBiotin-labeled tetra-acetylated histone H4 peptide (H4Ac4) and BRD4-BD1or BRD4-BD2 protein at concentration less than 1 nM. The incubation for75 min. was followed by the addition of 20 μL of assay buffersupplemented with Streptavidin donor beads (PerkinElmer 6760002) and GSHAcceptor beads (PerkinElmer-AL109C) at final concentration 2-4 μg/mLunder reduced light. After plate sealing, the plate was incubated in thedark at room temperature for 75 min. before reading on a PHERAstar FSplate reader (BMG Labtech). IC₅₀ determination was performed by fittingthe curve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

IC₅₀ data for the Examples is presented in Table 13 as determined byAssay A1 (column symbols: + refers to ≤100 nM; ++ refers to >100 nM and≤1000 nM; +++ refers to >1000 nM and ≤10,000 nM).

TABLE 13 BRD4-BD1 BRD4-BD2 Ex. No. IC₅₀ (nM) IC₅₀ (nM)  1 + +  2 + +  3++ +  4 ++ +  5 ++ +  6 + +  7 + +  8 ++ +  9 + +  9A + +  9B + + 10 + +11 ++ ++ 12 ++ + 13 ++ + 14 ++ + 15 + + 16 ++ + 17 ++ + 18 ++ + 19 ++ +20 + + 21 ++ + 22 ++ + 23 + + 24 + + 24A + + 24B + + 25 + + 26 + +27 + + 28 ++ + 29 + + 30 + + 31 + + 32 ++ + 33 + + 34 + + 35 + + 35A + +35B + + 36 + + 37 + + 38 ++ + 39 + + 40 + + 41 + + 42 + + 42A + +42B + + 43 ++ + 44 + + 44A + + 44B + + 45 + + 46 + + 47 + + 47A + +47B + + 48 + + 49 + + 50 + + 51 + + 52 + + 53 + + 54 + + 55 + + 56 + +57 + + 58 + + 59 + + 60 + + 61 + + 62 + + 63 + + 64 + + 65 + + 66 + +67 + + 68 + + 69 + + 70 + + 71 + + 72 + + 73 + + 74 + + 75 + + 76 + +77 + + 78 + + 79 + + 80 + + 81 + + 82 + + 83 + + 83A + + 83B + + 84 + +

Example B1: KMS.12.BM Cell Viability Assay

KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka,Japan) and maintained in RPMI with 10% FBS culture medium. To measurethe cytotoxic activity of the compounds through ATP quantitation, theKMS.12.BM cells are plated in the RPMI culture medium at 5000cells/well/per 100 μL into a 96-well polystyrene clear black tissueculture plate (Greiner-bio-one through VWR, NJ), in the presence orabsence of a concentration range of test compounds. After 3 days, 100 mLCell Titer-GLO Luminescent (Promega, Madison, Wis.) cell culture agentis added to each well for 10 minutes at room temperature to stabilizethe luminescent signal. This determines the number of viable cells inculture based on quantitation of the ATP present, which signals thepresence of metabolically active cells. Luminescence is measured withthe Top Count 384 (Packard Bioscience through Perkin Elmer, Boston,Mass.). Compound inhibition is determined relative to cells culturedwith no drug and the IC₅₀ is reported as the compound concentrationrequired for 50% cell death. IC₅₀ data for the Examples is presented inTable 14 as determined by Assay B1 (column symbols: + refers to ≤1000nM; ++ refers to >1000 nM and ≤10,000 nM; NA indicates that data was notavailable).

TABLE 14 KMS.12.BM Ex. No. IC₅₀ (nM)  1 +  2 +  3 +  4 +  5 +  6 +  7 + 8 +  9 +  9A +  9B + 10 + 11 NA 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 +20 + 21 + 22 ++ 23 ++ 24 + 24A + 24B + 25 + 26 + 27 + 28 + 29 + 30 +31 + 32 + 33 + 34 + 35 + 35A + 35B + 36 + 37 + 38 NA 39 NA 40 + 41 +42 + 42A + 42B + 43 NA 44 + 44A + 44B + 45 + 46 + 47 + 47A + 47B + 48 +49 + 50 + 51 + 52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 +63 + 64 + 65 + 66 + 67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 +77 + 78 + 79 + 80 + 81 + 82 + 83 + 83A + 83B + 84 +

Example C1: KMS.12.BM C-myc ELISA Assay

KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka,Japan) and maintained in RPMI with 10% FBS culture medium. To measurethe C-myc inhibitory activity of the compounds, the KMS.12.BM cells areplated in the RPMI culture medium at 75000 cells/well/per 200 μL into a96-well flat bottom polystyrene tissue culture plate (Corning throughVWR, N.J.), in the presence or absence of a concentration range of testcompounds. After 2 hours, cell are pelleted and lysed with CellExtraction Buffer (BioSource, Carlsbad, Calif.) in the presence ofprotease inhibitors (Life Technologies, Grand Island, N.Y. and Sigma, StLouis, Mo.). Clarified lyses are tested in a C-myc commercial ELISA(Life Technologies, Grand Island, N.Y.). Compound inhibition isdetermined relative to cells cultured with no drug and the IC₅₀ isreported as the compound concentration required for 50% C-mycinhibition.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A method of treating an autoimmune orinflammatory disease, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a compound ofFormula IIIa:

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areeach independently selected from H, methyl, ethyl, propyl, cyclopropyl,cyclopentyl, pyran-4-yl, phenyl, pyridin-2-yl, 2-chloro-4-phenyl,2-chloro-4-fluorophenyl, and 2-hydroxyethyl; or R¹ and R² together withthe carbon atom to which they are attached form cyclopropyl; R³ is H,methyl, ethyl, or propyl, wherein said methyl is optionally substitutedwith cyclopropyl, pyridinyl, —C(═O)NH₂, —C(═O)NHCH₃,—C(═O)(4-methylpiperazin-1-yl), —C(═O)NH(4-methylpiperazin-1-yl), or—C(═O)OH; R⁵ is H, 1-methyl-1H-pyrazol-4-yl, 2-furyl, CN, NO₂, methoxy,—C(═O)NH₂, —C(═O)NH(CH₃), —C(═O)N(CH₃)₂, —C(═O)-(morpholin-4-yl),—C(═O)CH₃, —CH₂OH, —CH₂OCH₃, —CH₂NH₂, —CH₂NHSO₂(CH₂CH₃), —CH₂NHC(═O)CH₃,—CH(OH)CH₃, —SO₂CH₃, —SO₂CH₂CH₃, —SO₂-(isopropyl), —SO₂N(CH₃)₂,—SO₂NH(CH₃), —SO₂—NH(isopropyl), or —SO₂-(piperidin-1-yl); and R⁷ ismethyl.
 2. The method of claim 1, wherein R¹ and R² are eachindependently selected from H, methyl, ethyl, propyl, cyclopropyl,cyclopentyl, pyran-4-yl, phenyl, pyridin-2-yl, 2-chloro-4-phenyl, and2-hydroxyethyl.
 3. The method of claim 1, wherein one of R¹ and R² is Hand the other is not H.
 4. The method of claim 1, wherein R¹ and R² areeach methyl, ethyl, or propyl.
 5. The method of claim 1, wherein R¹ andR² are each methyl.
 6. The method of claim 1, wherein R³ is H, methyl,ethyl, or propyl, wherein said methyl is optionally substituted withcyclopropyl, pyridinyl, —C(═O)NHCH₃, —C(═O)NH(4-methylpiperazin-1-yl),or —C(═O)OH.
 7. The method of claim 1, wherein R³ is methyl.
 8. Themethod of claim 1, wherein R⁵ is —SO₂CH₃, —SO₂CH₂CH₃, —SO₂-(isopropyl),—SO₂N(CH₃)₂, —SO₂NH(CH₃), —SO₂—NH(isopropyl), or —SO₂-(piperidin-1-yl).9. The method of claim 1, wherein R⁵ is S(O)₂CH₃.
 10. The method ofclaim 1, wherein R⁵ is S(O)₂CH₂CH₃.
 11. The method of claim 1, whereinthe compound is selected from:8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-ethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-pyridin-2-yl-2H-1,4-benzoxazin-3(4H)-one2,2,2-trifluoroacetate;2-cyclopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-ethyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-6-methoxy-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]aceticacid;2-[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-N-methylacetamide;2-[2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetamide;2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-4-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one;2,4-diisopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide;2-isopropyl-N-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-nitro-2H-1,4-benzoxazin-3(4H)-one;2-cyclopropyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one;2-(2-chloro-4-fluorophenyl)-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-methoxy-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-1,4-benzoxazin-3(4H)-one;8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one;2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(morpholin-4-ylcarbonyl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-N,N-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide;2-cyclopentyl-6-methoxy-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(hydroxymethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-6-(methoxymethyl)-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(Aminomethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;N-{[2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]methyl}ethanesulfonamide;N-{[2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]methyl}acetamide;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide;6-(2-furyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2-phenyl-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;2-(2-hydroxyethyl)-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;6-acetyl-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(1-hydroxyethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(ethylsulfonyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-6-(isopropylsulfonyl)-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;4-(cyclopropylmethyl)-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;4-ethyl-2-isopropyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;6-(ethylsulfonyl)-2-isopropyl-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;2-isopropyl-6-(isopropylsulfonyl)-4-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)spiro[1,4-benzoxazine-2,1′-cyclopropan]-3(4H)-one;2-isopropyl-N,N-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;2-isopropyl-N-methyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;N,N,2,2,4-pentamethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;N,N,2,2-tetramethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;2-isopropyl-N,N,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(piperidin-1-ylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(piperidin-1-ylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;N-isopropyl-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one;6-(ethylsulfonyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(isopropylsulfonyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(ethylsulfonyl)-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(isopropylsulfonyl)-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-acetyl-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-(1-hydroxyethyl)-2,2-dimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;6-acetyl-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;and6-(1-hydroxyethyl)-2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2H-1,4-benzoxazin-3(4H)-one;or a pharmaceutically acceptable salt of any of the aforementioned. 12.The method of claim 1, wherein the autoimmune or inflammatory disease isselected from allergy, allergic rhinitis, arthritis, asthma, chronicobstructive pulmonary disease, degenerative joint disease, dermatitis,organ rejection, eczema, hepatitis, inflammatory bowel disease, multiplesclerosis, myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septicshock, systemic lupus erythematosus, tissue graft rejection, and type Idiabetes.
 13. A method of treating an autoimmune or inflammatorydisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-oneor a pharmaceutically acceptable salt thereof.
 14. The method of claim13, wherein the autoimmune or inflammatory disease is selected fromallergy, allergic rhinitis, arthritis, asthma, chronic obstructivepulmonary disease, degenerative joint disease, dermatitis, organrejection, eczema, hepatitis, inflammatory bowel disease, multiplesclerosis, myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septicshock, systemic lupus erythematosus, tissue graft rejection, and type Idiabetes.
 15. The method of claim 1, wherein the autoimmune orinflammatory disease is an autoimmune disease.
 16. The method of claim1, wherein the autoimmune or inflammatory disease is an inflammatorydisease.
 17. The method of claim 1, wherein the autoimmune orinflammatory disease is associated with a BET protein.
 18. The method ofclaim 1, wherein the compound is2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-oneor a pharmaceutically acceptable salt thereof.
 19. The method of claim12, wherein the compound is2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-oneor a pharmaceutically acceptable salt thereof.